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WO2019001549A1 - Multi-arm single molecular weight polyethylene glycol, active derivative thereof, preparation therefor, and application thereof - Google Patents

Multi-arm single molecular weight polyethylene glycol, active derivative thereof, preparation therefor, and application thereof Download PDF

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Publication number
WO2019001549A1
WO2019001549A1 PCT/CN2018/093523 CN2018093523W WO2019001549A1 WO 2019001549 A1 WO2019001549 A1 WO 2019001549A1 CN 2018093523 W CN2018093523 W CN 2018093523W WO 2019001549 A1 WO2019001549 A1 WO 2019001549A1
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WIPO (PCT)
Prior art keywords
group
integer
molecular weight
polyethylene glycol
combination
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Ceased
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PCT/CN2018/093523
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French (fr)
Chinese (zh)
Inventor
魏真
林美娜
赵宣
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Jenkem Technology Co Ltd
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Jenkem Technology Co Ltd
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Publication of WO2019001549A1 publication Critical patent/WO2019001549A1/en
Priority to US16/729,653 priority Critical patent/US11518728B2/en
Anticipated expiration legal-status Critical
Priority to US18/047,454 priority patent/US12331016B2/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/305—Saturated compounds containing more than one carboxyl group containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C31/18—Polyhydroxylic acyclic alcohols
    • C07C31/20—Dihydroxylic alcohols
    • C07C31/202—Ethylene glycol
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
    • C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
    • C08G65/3322—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof acyclic
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to the technical field of polyethylene glycol functional materials, in particular to a multi-arm single molecular weight polyethylene glycol and a reactive derivative thereof, and a preparation and application thereof, in particular, a preparation of a drug conjugate, a gel material, a drug carrier and Applications in medical device products.
  • the functionalized polyethylene glycol is grafted onto a biologically active molecule such as a drug, which can improve the water solubility, biocompatibility and stability of the drug and the like, and can reduce the toxicity of the drug.
  • Functionalized polyethylene glycols have been widely used in biomedical fields as bioactive molecular modifiers. Although the molecular weight distribution of the currently synthesized polyethylene glycol product is already quite narrow, it is still a mixture of polyethylene glycols of different molecular weights, and the impurities contained therein often lead to difficulty in ensuring the repeatability of the bioactive molecular modification process.
  • the multi-arm single-molecular weight PEG product can effectively increase the drug loading per unit; at the same time, since the terminal position of the multi-arm product can be heterofunctional, two or even three drugs can be simultaneously connected in one molecular system. It can be used as a drug for multiple diseases; it can also be used as a linker in the ADC system, thereby greatly increasing the drug loading of a single ADC molecule.
  • multi-arm polyethylene glycol can be used as a crosslinking agent in the production of gels, which can be used as adhesives, penetration inhibitors, anti-blocking agents and hemostatic materials in medical devices. .
  • Multi-arm single molecular weight PEG and its derivatives have broad application prospects. However, due to the difficulty in synthesizing the multi-arm single-molecular weight PEG product, the synthesis cost is high and it is difficult to scale production.
  • the inventors of the present invention have devised a multi-arm single molecular weight polyethylene glycol and a reactive derivative thereof for preparing a gel or combining with a drug molecule to prepare a drug conjugate and a pharmaceutical composition. .
  • the invention provides a compound having the structure:
  • A is a core structure and is a polyol group selected from the group consisting of: pentaerythritol, oligo-pentaerythritol, glycerol and oligoglycerol residues and glyceryl ether groups thereof,
  • X 1 is a linking group selected from the group consisting of: -(CH 2 ) i -, -(CH 2 ) i O-, -(CH 2 ) i NHCO-, -(CH 2 ) i CONH-, -(CH 2 ) i OCO- and -(CH 2 ) i COO-, one or a combination of two or more, i is an integer from 1 to 10 (specifically, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10),
  • Y is a terminal group selected from the group consisting of a hydroxyl group, a carboxyl group, an ester group, a ketone group, an amino group, a fluorenyl group, a maleimide group, an alkynyl group, and an azide group.
  • n is an integer from 3 to 24.
  • the A has the following structure:
  • B has the following structure:
  • r is an integer from 1 to 5 (specifically 1, 2, 3, 4 or 5),
  • a, b, c and d are integers, independently selected from 0 and 1.
  • the A has the following structure:
  • B has the following structure:
  • s is an integer from 1 to 5 (specifically 1, 2, 3, 4 or 5),
  • e, f and g are integers independently selected from 0 and 1.
  • the r is 1, 2 or 3.
  • said a, b, c and d are both zero.
  • the a, b, c, and d are all 1.
  • the s is 1, 2 or 3.
  • the e, f, and g are both zero.
  • said e, f and g are both 1.
  • the A has the following structure:
  • the A has the following structure:
  • the A has the following structure:
  • the A has the following structure:
  • the A has the following structure:
  • the A has the following structure:
  • n is an integer from 3 to 16, specifically 3, 4, 5, 6, 7, 8, 10, 12, 14, or 16.
  • the i is an integer from 1 to 5, specifically 1, 2, 3, 4 or 5, preferably 1, 2 or 3.
  • the X 1 is selected from the group consisting of: -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CONHCH 2 -, and -CH 2 CONHCH 2 CH 2 - one or a combination of two or more.
  • said X 1 is -CH 2 CH 2 -.
  • the ester group is selected from the group consisting of: One of them.
  • the ketone group is selected from the group consisting of: One of -COCH 3 and -COCH 2 CH 3 .
  • said Y is -COOH.
  • the -X 1 -Y is -CH 2 CH 2 COOH.
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • Another aspect of the present invention also provides a multi-arm single molecular weight polyethylene glycol having the following structure:
  • R is a linking group selected from the group consisting of: -NHCO-, -CONH-, -OCO-, -COO-, -O-, One or a combination of two or more,
  • X 2 is a linking group selected from the group consisting of: -(CH 2 ) j -, -(CH 2 ) j O-, -(CH 2 ) j CO-, -(CH 2 ) j NH-, -(CH 2 ) j NHCO-, -(CH 2 ) j CONH-, -(CH 2 ) j OCO- and -(CH 2 ) j COO- one or a combination of two or more, j is an integer from 0 to 10, (specific Such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10),
  • PEG has the following structure: -(CH 2 CH 2 O) m -, m is an integer from 4 to 200,
  • n is an integer from 3 to 24.
  • the R is selected from the group consisting of: -NHCO-, -CONH-, One or a combination of two or more.
  • said R is -NHCO- or -CONH-.
  • the j is an integer of 0-5, specifically 0, 1, 2, 3, 4 or 5, preferably 0, 1, 2 or 3.
  • the X 2 is selected from the group consisting of: a single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CONHCH 2 -, and -CH 2 One or a combination of two or more of CONHCH 2 CH 2 -.
  • said X 2 is a single bond.
  • the -X 1 -RX 2 - is -CH 2 CH 2 CONH-.
  • m is an integer of 4 to 200, such as an integer of 4 to 100 (specifically, 4, 5, 6, 7, 8, 9, 10, 11, 12) , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or 100), 100- An integer of 200 (specifically 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200), preferably an integer from 4 to 100.
  • the m is 4, 12 or 24.
  • the multi-arm single molecular weight polyethylene glycol has the following structure:
  • m is 4.
  • m is 12.
  • m is 24.
  • the multi-arm single molecular weight polyethylene glycol has the following structure:
  • m is 4.
  • m is 12.
  • m is 24.
  • the multi-arm single molecular weight polyethylene glycol has the following structure:
  • m is 4 in formula IV-3.
  • m is 12.
  • m is 24.
  • the multi-arm single molecular weight polyethylene glycol has the following structure:
  • m is 4.
  • m is 24.
  • the multi-arm single molecular weight polyethylene glycol has the following structure:
  • m is 4.
  • m is 12.
  • m is 24.
  • the multi-arm single molecular weight polyethylene glycol has the following structure:
  • m is 4.
  • m is 12 in Formula IV-6.
  • m is 24.
  • the above compounds of the present invention can be used as linkers for the preparation of other multi-arm structures, such as multi-arm polyethylene glycols, particularly the above-described multi-arm single molecular weight polyethylene glycols of the present invention.
  • Another aspect of the present invention provides a method for producing the above multi-arm single molecular weight polyethylene glycol, which comprises the compound of the present invention
  • the step of reacting with WX 2 -PEG-PG, the reaction formula is as follows:
  • W is a terminal group selected from the group consisting of a hydroxyl group, a carboxyl group, an ester group, a ketone group, an amino group, a fluorenyl group, a maleimide group, an alkynyl group, and an azide group.
  • PG is a hydroxy protecting group
  • Y is a carboxyl group
  • W is an amino group
  • Y is an amino group and W is a carboxyl group.
  • the Y is a hydroxyl group
  • W is a carboxyl group
  • the Y is a carboxyl group and W is a hydroxyl group.
  • Y is an ester or ketone group
  • W is an amino group
  • Y is an amino group
  • W is an ester group or a ketone group
  • the Y is a maleimide group
  • W is a fluorenyl group
  • the Y is a fluorenyl group and W is a maleimide group.
  • Y is an alkynyl group
  • W is an azide group
  • Y is an azide group
  • W is an alkynyl group
  • -CH 3 , -C(CH 3 ) 3 -CH 2 OCH 3 , -COCH 3 , -COC(CH 3 ) 3
  • the method further comprises the step of a hydroxyl deprotection reaction, the reaction formula being as follows:
  • Another aspect of the present invention provides a living derivative of the above multi-arm single molecular weight polyethylene glycol having the following structure:
  • X 3 is a linking group selected from the group consisting of: -(CH 2 ) k -, -(CH 2 ) k O-, -(CH 2 ) k CO-, -(CH 2 ) k NH-, -(CH 2 ) k NHCO -, - (CH 2 ) k CONH -, - (CH 2) k NHCONH -, - (CH 2) k OCO -, - (CH 2) k COO -, - (CH 2) k OCOO- and - (CH 2 ) k OCONH- one or a combination of two or more, k is an integer from 0 to 10,
  • HA is a halogen atom (specifically -F, -Cl, -Br or -I),
  • E is a C1-10 hydrocarbon group or a fluorine atom-containing C1-10 hydrocarbon group
  • L 1-3 is the same or different C1-10 alkyl group or C1-6 alkoxy group.
  • the k is an integer from 1 to 5, specifically 1, 2, 3, 4 or 5, preferably 1, 2 or 3.
  • the X 3 is selected from the group consisting of: a single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 O-, -CH 2 One or a combination of two or more of CH 2 O-, -CH 2 CONHCH 2 -, and -CH 2 CONHCH 2 CH 2 -.
  • said X 3 is a single bond or -CH 2 -.
  • the Z is selected from the group consisting of: -H, -NH 2 , -SH, -N 3 , -Br, -CONH 2 , -COOH, -CHO, -COCl, -COBr, -C ⁇ CH, One of them.
  • the F is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the active derivative including the F -H and -CH 2 COOH.
  • the multi-arm single molecular weight polyethylene glycol reactive derivative has the structure:
  • F 11-14 is the same or different -X 3 -Z type structure.
  • m is 4.
  • m is 12.
  • m is 24.
  • F 11-14 includes -H and -CH 2 COOH.
  • F 11-13 is both -H and F 14 is -CH 2 COOH.
  • F 11 and F 12 are -H
  • F 13 and F 14 are -CH 2 COOH.
  • F 11-14 includes -H and -NH 2.
  • F 11-13 is both -H and F 14 is -NH 2 .
  • F 11 and F 12 are -H
  • F 13 and F 14 are -NH 2 .
  • m is 24, F 11 and F 12 are -H, and F 13 and F 14 are -CH 2 COOH.
  • the multi-arm single molecular weight polyethylene glycol reactive derivative has the structure:
  • F 21-26 is the same or different -X 3 -Z type structure.
  • m is 4.
  • m is 12.
  • m is 24.
  • F 21-26 are integers in formula V-2.
  • F 21-26 includes -H and -CH 2 COOH.
  • F 21-25 is both -H and F 26 is -CH 2 COOH.
  • F 21-26 includes -H and -NH 2.
  • F 21-25 is both -H and F 26 is -NH 2 .
  • the multi-arm single molecular weight polyethylene glycol reactive derivative has the structure:
  • F 31-38 are the same or different -X 3 -Z type structures.
  • m is 4.
  • m is 24.
  • F 31-38 includes -H and -CH 2 COOH.
  • F 31-37 are both -H and F 38 is -CH 2 COOH.
  • F 31-37 are both -H and F 38 is -NH 2 .
  • the multi-arm single molecular weight polyethylene glycol reactive derivative has the structure:
  • F 41-48 are the same or different -X 3 -Z type structures.
  • m is 4.
  • m is 24.
  • F 41-48 includes -H and -CH 2 COOH.
  • F 41-47 are both -H and F 48 is -CH 2 COOH.
  • F F 41-47 are both -H and F 48 is -NH 2 .
  • the multi-arm single molecular weight polyethylene glycol reactive derivative has the structure:
  • F 51-53 is the same or different -X 3 -Z type structure.
  • m is 4.
  • m is 24.
  • the multi-arm single molecular weight polyethylene glycol reactive derivative has the structure:
  • F 61-64 are the same or different -X 3 -Z type structures.
  • m is 4.
  • m is 24.
  • Another aspect of the invention also provides a gel formed from the above multi-arm single molecular weight polyethylene glycol active derivative.
  • Another aspect of the present invention also provides a combination of the above multi-arm single molecular weight polyethylene glycol and a drug molecule.
  • Another aspect of the present invention also provides a combination of the above multi-arm single molecular weight polyethylene glycol active derivative and a drug molecule.
  • the drug molecule is selected from the group consisting of amino acids, polypeptides, proteins, nucleosides, sugars, organic acids, flavonoids, terpenoids, terpenoids, phenylpropanol Classes, steroids and their glycosides and alkaloids and combinations thereof.
  • the drug molecule is selected from the group consisting of: chlorambucil, cisplatin, 5-fluorouracil, paclitaxel, doxorubicin, methotrexate, ennotecan and more One or more of the paclitaxel.
  • the drug molecule is selected from the group consisting of: interferon, interleukin, tumor necrosis factor, growth factor, colony stimulating factor, erythropoietin, and superoxide dismutase A variety.
  • the drug molecule is docetaxel.
  • the drug molecule is INOTEC.
  • the multi-arm single molecular weight polyethylene glycol reactive derivative is an eight-arm polyethylene glycol acetate.
  • the combination of the invention is a combination of eight-arm polyethylene glycol acetate with enonotecan or docetaxel.
  • Another aspect of the invention also provides a pharmaceutical composition comprising the above conjugate and a pharmaceutically acceptable additive.
  • the additive may be any one or more of an excipient, a disintegrant, a binder, a lubricant, a suspending agent, a stabilizer, a filler, a binder, and the like.
  • excipient examples include lactose, mannitol, isomalt, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, and the like;
  • examples of the disintegrator include low-substituted hydroxypropylcellulose, cross-linked vitamins Ketones, sodium starch glycolate, croscarmellose sodium, starch, etc.;
  • examples of binders include hydroxypropylcellulose, hypromellose, povidone, copovidone and pregelatinized starch Etc.
  • the lubricant examples include stearic acid, magnesium stearate, and sodium fumarate, and the like;
  • examples of the wetting agent include polyoxyethylene sorbitan fatty acid ester, poloxamer, and poly Oxyethylene castor oil derivatives and the like;
  • examples of suspending agents include hypromellose, hydroxypropylcellulose, povidone, copovidone, sodium carboxymethylcellulose, methylcellulose, and the like; stabilizers Examples include citric acid, fumaric acid, succinic acid and the like;
  • examples of the filler include starch, sucrose, lactose, and microcrystalline cellulose; and examples of the binder include cellulose derivatives, alginate, gelatin, and poly Vinyl pyrrolidone and the like.
  • the pharmaceutical composition of the present invention may further include any one or more of an anti-coagulant, a flavor enhancer, an emulsifier, a preservative, and the like.
  • the pharmaceutical composition of the present invention may be a tablet (including a sugar-coated tablet, a film-coated tablet, a sublingual tablet, an orally disintegrating tablet, an oral tablet, etc.), a pill, a powder, a granule, a capsule.
  • compositions including soft capsules and microcapsules, etc.
  • lozenges syrups, liquids, emulsions, suspensions, controlled release preparations (for example, transient release preparations, sustained release preparations and sustained release microcapsules), aerosols, films (for example, an oral disintegrating film, an oral mucosa-adhesive film), an injection (for example, subcutaneous injection, intravenous injection, intramuscular injection, and intraperitoneal injection), an intravenous drip, a transdermal absorption preparation, an ointment, Lotions, adhesive preparations, suppositories (eg, rectal suppositories and pessaries, etc.), small pills, nasal preparations, pulmonary preparations (inhalation), eye drops, etc., oral or parenteral preparations (eg, intravenous, Administration forms such as intramuscular, subcutaneous, intra-organ, intranasal, intradermal, instillation, intracerebral and rectal administration, administration to the vicinity of the
  • Another aspect of the present invention also provides the use of the above compound in the preparation of a multi-arm polyethylene glycol, a multi-arm polyethylene glycol active derivative, and a pharmaceutical combination thereof, and a pharmaceutical composition.
  • the multi-arm polyethylene glycol is the multi-arm single molecular weight polyethylene glycol of the invention described above.
  • the multi-arm polyethylene glycol reactive derivative is the above-described multi-arm single molecular weight polyethylene glycol active derivative of the invention.
  • Another aspect of the present invention provides a use of the above multi-arm single molecular weight polyethylene glycol in the preparation of a multi-arm polyethylene glycol active derivative, a pharmaceutical combination thereof, and a pharmaceutical composition.
  • Another aspect of the present invention also provides the use of the above multi-arm single molecular weight polyethylene glycol active derivative for the preparation of gels, drug conjugates and pharmaceutical compositions.
  • Another aspect of the invention also provides the use of the above gel in the preparation of a pharmaceutical carrier and a medical device product.
  • the medical device product is selected from one or more of the group consisting of: a binder, a barrier agent, an anti-blocking agent, and a hemostatic material.
  • Another aspect of the present invention provides a multi-arm single molecular weight polyethylene glycol, a multi-arm single molecular weight polyethylene glycol active derivative, and a pharmaceutical combination thereof, a pharmaceutical composition, a gel, and a preparation for prevention and/or treatment.
  • the multi-arm single molecular weight polyethylene glycol and the reactive derivative thereof provided by the invention are single molecular weight compounds, avoiding the application of the high molecular polymer mixture in the prior art, and effectively improving the purity of the drug.
  • the multi-arm single molecular weight polyethylene glycol and its active derivative are used for drug modification, which can effectively improve the solubility, stability and immunogenicity of the drug, improve the absorption of the drug in vivo, prolong the half-life of the drug, and improve the bioavailability of the drug. Degree, enhance efficacy, reduce toxic side effects.
  • the gel formed by the multi-arm single molecular weight polyethylene glycol active derivative provided by the invention can be used for preparing a controlled release drug, prolonging the action time of the drug, reducing the number of administrations, and improving patient compliance.
  • protecting group means a substituent which is generally used to prevent or protect a specific functional group when other functional groups of the compound react.
  • hydroxy protecting group refers to a substituent attached to a hydroxyl group that blocks or protects a hydroxyl functional group.
  • Commonly used hydroxyl protecting groups include an acetyl group, a trialkylsilyl group, and the like.
  • pharmaceutically acceptable refers to an allergic reaction or the like which is physiologically compatible after administration to a human and does not cause gastrointestinal disorders such as dizziness.
  • prevention includes therapeutic or prophylactic treatment or measures with the goal of preventing or slowing down a targeted pathological condition or disorder.
  • a subject is successfully "prevented” if, after receiving a therapeutic amount of the fusion protein of the invention according to the method of the invention, the subject exhibits a decrease or disappearance of one or more signs and symptoms of a particular disease that is observable and/or measurable "or "treatment.”
  • the compounds used in the present invention are either commercially available or can be prepared according to the disclosed preparation methods, which do not limit the therapeutic range of the present invention.
  • Pentaerythritol (1 mol), potassium t-butoxide (0.01 mol), and DMF were added to a three-necked flask, and the mixture was stirred. Then, tert-butyl acrylate (5 mol) was added dropwise to the reaction solution to react at room temperature overnight. After the completion of the reaction, the mixture was filtered, and the reaction mixture was evaporated to dryness, and a silica gel column was used to obtain a crude product of tert-butyl tetraacrylate instead of pentaerythritol.
  • the tert-butyl tetraacrylate substituted pentaerythritol was dissolved in a dichloromethane solution containing 50% TFA and allowed to react at room temperature overnight. After the completion of the reaction, the reaction solution was spin-dried, and acetonitrile was recrystallized to obtain a pure tetrakis acid-substituted pentaerythritol.
  • Pentaerythritol tetraglyceride (1 mol), potassium t-butoxide (0.01 mol), and DMF were added to a three-necked flask, and the mixture was stirred. Then, tert-butyl acrylate (10 mol) was added dropwise to the reaction solution to react at room temperature overnight. After the completion of the reaction, the mixture was filtered, and the reaction mixture was evaporated to dryness, and a column of silica gel column was used to obtain a pure product of tert-butyl octaacrylate and pentaerythritol glycerol ether.
  • the pure tert-butyl octaacrylate substituted pentaerythritol glyceryl ether was dissolved in a dichloromethane solution containing 50% TFA and allowed to react at room temperature overnight. After the completion of the reaction, the reaction solution was spin-dried, and acetonitrile was recrystallized to obtain a pure product of octaacrylic acid substituted pentaerythritol glyceryl ether.
  • the 4ARM-(EG 24 -OTr) 4 pure product was dissolved in 8% TFA in dichloromethane, and reacted at room temperature overnight, and an appropriate amount of 0.1 g/ml sodium hydroxide solution was added under ice bath, and then reacted at room temperature for 3 hours. .
  • the pH of the reaction solution was adjusted to 6.5-7 with 1N hydrochloric acid, then the appropriate amount of sodium chloride was added, and the mixture was extracted twice with dichloromethane, and the dichloromethane phase was spun, and then the appropriate amount of water was added to dissolve the dichloromethane.
  • the filtrate was again collected by filtration, and the filtrate was dried to give the product 4ARM-(EG 24 -OH) 4 .
  • the 4ARM-(EG 12 -OTr) 4 pure product was dissolved in 8% TFA in dichloromethane, and reacted at room temperature overnight, and an appropriate amount of 0.1 g/ml sodium hydroxide solution was added under ice bath, and then reacted at room temperature for 3 hours. .
  • the pH of the reaction solution was adjusted to 6.5-7 with 1N hydrochloric acid, then the appropriate amount of sodium chloride was added, and the mixture was extracted twice with dichloromethane, and the dichloromethane phase was spun, and then the appropriate amount of water was added to dissolve the dichloromethane.
  • the filtrate was again collected by filtration, and the filtrate was dried to give the product 4ARM-(EG 12 - OH) 4 .
  • the 8ARM-(EG 4 -OTr) 4 pure product was dissolved in 8% TFA in dichloromethane, and reacted at room temperature overnight, and an appropriate amount of 0.1 g/ml sodium hydroxide solution was added under ice bath, and then reacted at room temperature for 3 hours. .
  • the pH of the reaction solution was adjusted to 6.5-7 with 1N hydrochloric acid, then the appropriate amount of sodium chloride was added, and the mixture was extracted twice with dichloromethane, and the dichloromethane phase was spun, and then the appropriate amount of water was added to dissolve the dichloromethane.
  • the filtrate was again collected by filtration, and the filtrate was dried to give the product 8ARM-(EG 4 -OH) 4 .

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Abstract

A multi-arm single molecular weight polyethylene glycol and an active derivative thereof, used for drug modification, effectively improving the solubility, stability, and immunogenicity of drugs; improving the absorption of the drugs in vivo, prolonging the half-life of the drugs, and improving bioavailability, enhancing efficacy, and reducing side effects of the drugs. The gel formed by the multi-arm single molecular weight polyethylene glycol active derivative can be used for the preparation of controlled release drugs, to prolong the action time of the drugs, to reduce the number of administrations, and to improve patient compliance.

Description

一种多臂单一分子量聚乙二醇及其活性衍生物及其制备和应用Multi-arm single molecular weight polyethylene glycol and active derivative thereof and preparation and application thereof 技术领域Technical field

本发明涉及聚乙二醇功能材料技术领域，具体涉及一种多臂单一分子量聚乙二醇及其活性衍生物及其制备和应用，特别是在制备药物结合物、凝胶材料、药物载体和医疗器械产品中的应用。The invention relates to the technical field of polyethylene glycol functional materials, in particular to a multi-arm single molecular weight polyethylene glycol and a reactive derivative thereof, and a preparation and application thereof, in particular, a preparation of a drug conjugate, a gel material, a drug carrier and Applications in medical device products.

背景技术Background technique

官能团化的聚乙二醇接枝到药物等生物活性分子上，可提高药物等的水溶性、生物相容性和稳定性，并可降低药物的毒性。官能团化的聚乙二醇作为生物活性分子改性剂已经在广泛应用于生物医药领域。虽然现在合成的聚乙二醇产品的分子量分布已经相当窄，但其仍旧是不同分子量聚乙二醇的混合物，其中含有的杂质往往导致对生物活性分子修饰过程的重复性难以保证。The functionalized polyethylene glycol is grafted onto a biologically active molecule such as a drug, which can improve the water solubility, biocompatibility and stability of the drug and the like, and can reduce the toxicity of the drug. Functionalized polyethylene glycols have been widely used in biomedical fields as bioactive molecular modifiers. Although the molecular weight distribution of the currently synthesized polyethylene glycol product is already quite narrow, it is still a mixture of polyethylene glycols of different molecular weights, and the impurities contained therein often lead to difficulty in ensuring the repeatability of the bioactive molecular modification process.

在药物等生物活性分子的研究应用中，避免引入混合物是普遍采用的策略，高纯度是最终产物追求的主要目标之一，因此，人们希望制备出高纯度的单一分子量PEG衍生物应用于药物等领域。目前，直链状的单一分子量PEG应用与生物医药领域已有一些报道，如低分子量的单一分子量PEG衍生物作为细胞毒素和抗体的连接体，可应用于抗体偶联药物(ADC)领域。In the research and application of bioactive molecules such as drugs, it is a common strategy to avoid the introduction of mixtures. High purity is one of the main goals pursued by the final product. Therefore, it is desirable to prepare high-purity single-molecular weight PEG derivatives for use in medicines, etc. field. At present, there are some reports on the application of linear single molecular weight PEG and biomedicine, such as low molecular weight single molecular weight PEG derivatives as a cytotoxin and antibody linker, which can be applied to the field of antibody-conjugated drugs (ADC).

与直链PEG产品相比，多臂的单一分子量PEG产品可有效提高单位载药量；同时，由于多臂产品的端位可为异官能团，一个分子体系中可以同时连接两种甚至三种药物，可以一药治多病；其还可以作为连接子应用于ADC体系中，从而大大提高单个ADC分子的载药量。此外，在医疗器械领域中，多臂聚乙二醇可作为交联剂，应用于制作凝胶，这些凝胶可在医疗器械中作为粘合剂、防渗透剂、防粘连剂和止血材料等。多臂单一分子量PEG及其衍生物拥有较为广阔的应用前景。但是，由于多臂单一分子量PEG产品的合成难度大，合成成本较高，难于规模化生产。Compared with the linear PEG product, the multi-arm single-molecular weight PEG product can effectively increase the drug loading per unit; at the same time, since the terminal position of the multi-arm product can be heterofunctional, two or even three drugs can be simultaneously connected in one molecular system. It can be used as a drug for multiple diseases; it can also be used as a linker in the ADC system, thereby greatly increasing the drug loading of a single ADC molecule. In addition, in the field of medical devices, multi-arm polyethylene glycol can be used as a crosslinking agent in the production of gels, which can be used as adhesives, penetration inhibitors, anti-blocking agents and hemostatic materials in medical devices. . Multi-arm single molecular weight PEG and its derivatives have broad application prospects. However, due to the difficulty in synthesizing the multi-arm single-molecular weight PEG product, the synthesis cost is high and it is difficult to scale production.

发明内容Summary of the invention

为克服现有技术的不足，本发明的发明人设计了一种多臂单一分子量聚乙二醇及其活性衍生物，用于制备凝胶，或与药物分子结合制备药物结合物和药物组合物。In order to overcome the deficiencies of the prior art, the inventors of the present invention have devised a multi-arm single molecular weight polyethylene glycol and a reactive derivative thereof for preparing a gel or combining with a drug molecule to prepare a drug conjugate and a pharmaceutical composition. .

本发明一方面提供一种化合物，其具有如下结构：In one aspect, the invention provides a compound having the structure:

Figure PCTCN2018093523-appb-000001
Figure PCTCN2018093523-appb-000001

其中，A为核心结构，为多元醇基，选自：季戊四醇、寡聚季戊四醇、丙三醇和寡聚丙三醇的残基及其甘油醚基，Wherein A is a core structure and is a polyol group selected from the group consisting of: pentaerythritol, oligo-pentaerythritol, glycerol and oligoglycerol residues and glyceryl ether groups thereof,

X 1为连接基团，选自：-(CH 2) i-、-(CH 2) iO-、-(CH 2) iNHCO-、-(CH 2) iCONH-、-(CH 2) iOCO-和-(CH 2) iCOO-中一种或两种以上的组合，i为1-10的整数(具体如0、1、2、3、4、5、6、7、8、9或10)， X 1 is a linking group selected from the group consisting of: -(CH 2 ) i -, -(CH 2 ) i O-, -(CH 2 ) i NHCO-, -(CH 2 ) i CONH-, -(CH 2 ) i OCO- and -(CH 2 ) i COO-, one or a combination of two or more, i is an integer from 1 to 10 (specifically, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10),

Y为端基，选自：羟基、羧基、酯基、酮基、氨基、巯基、马来酰亚胺基、炔基和叠氮基中的一种，Y is a terminal group selected from the group consisting of a hydroxyl group, a carboxyl group, an ester group, a ketone group, an amino group, a fluorenyl group, a maleimide group, an alkynyl group, and an azide group.

n为3-24的整数。n is an integer from 3 to 24.

在本发明的一个实施例中，所述A具有如下结构：In one embodiment of the invention, the A has the following structure:

Figure PCTCN2018093523-appb-000002
Figure PCTCN2018093523-appb-000002

其中，B具有如下结构：

Figure PCTCN2018093523-appb-000003
Among them, B has the following structure:
Figure PCTCN2018093523-appb-000003

r为1-5的整数(具体可为1、2、3、4或5)，r is an integer from 1 to 5 (specifically 1, 2, 3, 4 or 5),

a、b、c和d为整数，独立地选自0和1。a, b, c and d are integers, independently selected from 0 and 1.

在本发明的另一个实施例中，所述A具有如下结构：In another embodiment of the invention, the A has the following structure:

Figure PCTCN2018093523-appb-000004
Figure PCTCN2018093523-appb-000004

其中，B具有如下结构：

Figure PCTCN2018093523-appb-000005
Among them, B has the following structure:
Figure PCTCN2018093523-appb-000005

s为1-5的整数(具体可为1、2、3、4或5)，s is an integer from 1 to 5 (specifically 1, 2, 3, 4 or 5),

e、f和g为整数，独立地选自0和1。e, f and g are integers independently selected from 0 and 1.

在本发明的一个实施例中，式Ⅱ中，所述r为1、2或3。In one embodiment of the invention, in Formula II, the r is 1, 2 or 3.

在本发明的一个实施例中，式Ⅱ中，所述a、b、c和d均为0。In one embodiment of the invention, in formula II, said a, b, c and d are both zero.

在本发明的一个实施例中，式Ⅱ中，所述a、b、c和d均为1。In one embodiment of the invention, in Formula II, the a, b, c, and d are all 1.

在本发明的一个实施例中，式Ⅲ中，所述s为1、2或3。In one embodiment of the invention, in Formula III, the s is 1, 2 or 3.

在本发明的一个实施例中，式Ⅲ中，所述e、f和g均为0。In one embodiment of the invention, in Formula III, the e, f, and g are both zero.

在本发明的一个实施例中，式Ⅲ中，所述e、f和g均为1。In one embodiment of the invention, in formula III, said e, f and g are both 1.

在本发明的一个实施例中，所述A具有如下结构：In one embodiment of the invention, the A has the following structure:

Figure PCTCN2018093523-appb-000006
Figure PCTCN2018093523-appb-000006

在本发明的一个实施例中，所述A具有如下结构：In one embodiment of the invention, the A has the following structure:

Figure PCTCN2018093523-appb-000007
Figure PCTCN2018093523-appb-000007

在本发明的一个实施例中，所述A具有如下结构：In one embodiment of the invention, the A has the following structure:

Figure PCTCN2018093523-appb-000008
Figure PCTCN2018093523-appb-000008

在本发明的一个实施例中，所述A具有如下结构：In one embodiment of the invention, the A has the following structure:

Figure PCTCN2018093523-appb-000009
Figure PCTCN2018093523-appb-000009

在本发明的一个实施例中，所述A具有如下结构：In one embodiment of the invention, the A has the following structure:

Figure PCTCN2018093523-appb-000010
Figure PCTCN2018093523-appb-000010

在本发明的一个实施例中，所述A具有如下结构：In one embodiment of the invention, the A has the following structure:

Figure PCTCN2018093523-appb-000011
Figure PCTCN2018093523-appb-000011

在本发明的一个实施例中，所述n为3-16的整数，具体可为3、4、5、6、7、8、10、12、14或16。In one embodiment of the invention, n is an integer from 3 to 16, specifically 3, 4, 5, 6, 7, 8, 10, 12, 14, or 16.

在本发明的一个实施例中，所述X 1中，所述i为1-5的整数，具体可为1、2、3、4或5，优选为1、2或3。 In an embodiment of the invention, in X 1 , the i is an integer from 1 to 5, specifically 1, 2, 3, 4 or 5, preferably 1, 2 or 3.

在本发明的一个实施例中，所述X 1选自：-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH 2CONHCH 2-和-CH 2CONHCH 2CH 2-中一种或两种以上的组合。 In one embodiment of the invention, the X 1 is selected from the group consisting of: -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CONHCH 2 -, and -CH 2 CONHCH 2 CH 2 - one or a combination of two or more.

在本发明的一个优选实施例中，所述X 1为-CH 2CH 2-。 In a preferred embodiment of the invention, said X 1 is -CH 2 CH 2 -.

在本发明的一个实施例中，所述Y中，所述酯基选自：

Figure PCTCN2018093523-appb-000012
Figure PCTCN2018093523-appb-000013
中的一种。 In an embodiment of the invention, in the Y, the ester group is selected from the group consisting of:
Figure PCTCN2018093523-appb-000012
Figure PCTCN2018093523-appb-000013
One of them.

在本发明的一个实施例中，所述Y中，所述酮基选自：

Figure PCTCN2018093523-appb-000014
-COCH 3和-COCH 2CH 3中的一种。 In an embodiment of the invention, in the Y, the ketone group is selected from the group consisting of:
Figure PCTCN2018093523-appb-000014
One of -COCH 3 and -COCH 2 CH 3 .

在本发明的一个优选实施例中，所述Y为-COOH。In a preferred embodiment of the invention, said Y is -COOH.

在本发明的一个更优选的实施例中，所述-X 1-Y为-CH 2CH 2COOH。 In a more preferred embodiment of the invention, the -X 1 -Y is -CH 2 CH 2 COOH.

在本发明的一个实施例中，所述化合物具有如下结构：In one embodiment of the invention, the compound has the structure:

Figure PCTCN2018093523-appb-000015
Figure PCTCN2018093523-appb-000015

在本发明的一个实施例中，所述化合物具有如下结构：In one embodiment of the invention, the compound has the structure:

Figure PCTCN2018093523-appb-000016
Figure PCTCN2018093523-appb-000016

在本发明的一个实施例中，所述化合物具有如下结构：In one embodiment of the invention, the compound has the structure:

Figure PCTCN2018093523-appb-000017
Figure PCTCN2018093523-appb-000017

在本发明的一个实施例中，所述化合物具有如下结构：In one embodiment of the invention, the compound has the structure:

Figure PCTCN2018093523-appb-000018
Figure PCTCN2018093523-appb-000018

在本发明的一个实施例中，所述化合物具有如下结构：In one embodiment of the invention, the compound has the structure:

Figure PCTCN2018093523-appb-000019
Figure PCTCN2018093523-appb-000019

在本发明的一个实施例中，所述化合物具有如下结构：In one embodiment of the invention, the compound has the structure:

Figure PCTCN2018093523-appb-000020
Figure PCTCN2018093523-appb-000020

本发明另一方面还提供一种多臂单一分子量聚乙二醇，其具有如下结构：Another aspect of the present invention also provides a multi-arm single molecular weight polyethylene glycol having the following structure:

Figure PCTCN2018093523-appb-000021
Figure PCTCN2018093523-appb-000021

其中，所述A和X 1具有本发明上述定义 Wherein A and X 1 have the above definition of the invention

R为连接基团，选自：-NHCO-、-CONH-、-OCO-、-COO-、-O-、

Figure PCTCN2018093523-appb-000022
Figure PCTCN2018093523-appb-000023
中的一种或两种以上的组合， R is a linking group selected from the group consisting of: -NHCO-, -CONH-, -OCO-, -COO-, -O-,
Figure PCTCN2018093523-appb-000022
Figure PCTCN2018093523-appb-000023
One or a combination of two or more,

X 2为连接基团，选自：-(CH 2) j-、-(CH 2) jO-、-(CH 2) jCO-、-(CH 2) jNH-、-(CH 2) jNHCO-、-(CH 2) jCONH-、-(CH 2) jOCO-和-(CH 2) jCOO-中一种或两种以上的组合，j为0-10的整数，(具体如0、1、2、3、4、5、6、7、8、9或10)， X 2 is a linking group selected from the group consisting of: -(CH 2 ) j -, -(CH 2 ) j O-, -(CH 2 ) j CO-, -(CH 2 ) j NH-, -(CH 2 ) j NHCO-, -(CH 2 ) j CONH-, -(CH 2 ) j OCO- and -(CH 2 ) j COO- one or a combination of two or more, j is an integer from 0 to 10, (specific Such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10),

PEG具有如下结构：-(CH 2CH 2O) m-，m为4-200的整数， PEG has the following structure: -(CH 2 CH 2 O) m -, m is an integer from 4 to 200,

n为3-24的整数。n is an integer from 3 to 24.

在本发明的一个实施例中，所述R选自：-NHCO-、-CONH-、

Figure PCTCN2018093523-appb-000024
Figure PCTCN2018093523-appb-000025
中的一种或两种以上的组合。 In one embodiment of the invention, the R is selected from the group consisting of: -NHCO-, -CONH-,
Figure PCTCN2018093523-appb-000024
Figure PCTCN2018093523-appb-000025
One or a combination of two or more.

在本发明的一个优选实施例中，所述R为-NHCO-或-CONH-。In a preferred embodiment of the invention, said R is -NHCO- or -CONH-.

在本发明的一个实施例中，所述X 2中，所述j为0-5的整数，具体可为0、1、2、3、4或5，优选为0、1、2或3。 In an embodiment of the present invention, in X 2 , the j is an integer of 0-5, specifically 0, 1, 2, 3, 4 or 5, preferably 0, 1, 2 or 3.

在本发明的一个实施例中，所述X 2选自：单键、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH 2CONHCH 2-和-CH 2CONHCH 2CH 2-中一种或两种以上的组合。 In one embodiment of the invention, the X 2 is selected from the group consisting of: a single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CONHCH 2 -, and -CH 2 One or a combination of two or more of CONHCH 2 CH 2 -.

在本发明的一个优选实施例中，所述X 2为单键。 In a preferred embodiment of the invention, said X 2 is a single bond.

在本发明的一个具体实施方式中，所述-X 1-R-X 2-为-CH 2CH 2CONH-。 In a specific embodiment of the invention, the -X 1 -RX 2 - is -CH 2 CH 2 CONH-.

本发明所述的多臂单一分子量聚乙二醇中，m为4-200的整数，如4-100的整数(具体可为4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、30、35、40、45、50、60、70、80、90或100)、100-200的整数(具体可为100、110、120、130、140、150、160、170、180、190或200)，优选为4-100的整数。In the multi-arm single-molecular weight polyethylene glycol according to the present invention, m is an integer of 4 to 200, such as an integer of 4 to 100 (specifically, 4, 5, 6, 7, 8, 9, 10, 11, 12) , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or 100), 100- An integer of 200 (specifically 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200), preferably an integer from 4 to 100.

在本发明的一个优选实施例中，所述m为4、12或24。In a preferred embodiment of the invention, the m is 4, 12 or 24.

在本发明的一个实施例中，所述多臂单一分子量聚乙二醇具有如下结构：In one embodiment of the invention, the multi-arm single molecular weight polyethylene glycol has the following structure:

Figure PCTCN2018093523-appb-000026
Figure PCTCN2018093523-appb-000026

在本发明的一个实施例中，式Ⅳ-1中，m为4。In one embodiment of the invention, in Formula IV-1, m is 4.

在本发明的一个实施例中，式Ⅳ-1中，m为12。In one embodiment of the invention, in formula IV-1, m is 12.

在本发明的一个实施例中，式Ⅳ-1中，m为24。In one embodiment of the invention, in formula IV-1, m is 24.

在本发明的一个实施例中，所述多臂单一分子量聚乙二醇具有如下结构：In one embodiment of the invention, the multi-arm single molecular weight polyethylene glycol has the following structure:

Figure PCTCN2018093523-appb-000027
Figure PCTCN2018093523-appb-000027

在本发明的一个实施例中，式Ⅳ-2中，m为4。In one embodiment of the invention, in Formula IV-2, m is 4.

在本发明的一个实施例中，式Ⅳ-2中，m为12。In one embodiment of the invention, in formula IV-2, m is 12.

在本发明的一个实施例中，式Ⅳ-2中，m为24。In one embodiment of the invention, in Formula IV-2, m is 24.

在本发明的一个实施例中，所述多臂单一分子量聚乙二醇具有如下结构：In one embodiment of the invention, the multi-arm single molecular weight polyethylene glycol has the following structure:

Figure PCTCN2018093523-appb-000028
Figure PCTCN2018093523-appb-000028

Figure PCTCN2018093523-appb-000029
Figure PCTCN2018093523-appb-000029

在本发明的一个实施例中，式Ⅳ-3中，m为4。In one embodiment of the invention, m is 4 in formula IV-3.

在本发明的一个实施例中，式Ⅳ-3中，m为12。In one embodiment of the invention, in formula IV-3, m is 12.

在本发明的一个实施例中，式Ⅳ-3中，m为24。In one embodiment of the invention, in formula IV-3, m is 24.

在本发明的一个实施例中，所述多臂单一分子量聚乙二醇具有如下结构：In one embodiment of the invention, the multi-arm single molecular weight polyethylene glycol has the following structure:

Figure PCTCN2018093523-appb-000030
Figure PCTCN2018093523-appb-000030

在本发明的一个实施例中，式Ⅳ-4中，m为4。In one embodiment of the invention, in Formula IV-4, m is 4.

在本发明的一个实施例中，式Ⅳ-4中，m为12。In one embodiment of the invention, in formula IV-4, m is 12.

在本发明的一个实施例中，式Ⅳ-4中，m为24。In one embodiment of the invention, in formula IV-4, m is 24.

在本发明的一个实施例中，所述多臂单一分子量聚乙二醇具有如下结构：In one embodiment of the invention, the multi-arm single molecular weight polyethylene glycol has the following structure:

Figure PCTCN2018093523-appb-000031
Figure PCTCN2018093523-appb-000031

在本发明的一个实施例中，式Ⅳ-5中，m为4。In one embodiment of the invention, in formula IV-5, m is 4.

在本发明的一个实施例中，式Ⅳ-5中，m为12。In one embodiment of the invention, in formula IV-5, m is 12.

在本发明的一个实施例中，式Ⅳ-5中，m为24。In one embodiment of the invention, in formula IV-5, m is 24.

在本发明的一个实施例中，所述多臂单一分子量聚乙二醇具有如下结构：In one embodiment of the invention, the multi-arm single molecular weight polyethylene glycol has the following structure:

Figure PCTCN2018093523-appb-000032
Figure PCTCN2018093523-appb-000032

在本发明的一个实施例中，式Ⅳ-6中，m为4。In one embodiment of the invention, in Formula IV-6, m is 4.

在本发明的一个实施例中，式Ⅳ-6中，m为12。In one embodiment of the invention, m is 12 in Formula IV-6.

在本发明的一个实施例中，式Ⅳ-6中，m为24。In one embodiment of the invention, in Formula IV-6, m is 24.

本发明上述化合物可作为连接子(linker)用于制备其他多臂结构的化合物，如多臂聚乙二醇，特别是本发明上述多臂单一分子量聚乙二醇。The above compounds of the present invention can be used as linkers for the preparation of other multi-arm structures, such as multi-arm polyethylene glycols, particularly the above-described multi-arm single molecular weight polyethylene glycols of the present invention.

本发明另一方面提供一种上述多臂单一分子量聚乙二醇的制备方法，所述方法包括本发明所述的化合物

Figure PCTCN2018093523-appb-000033
与W-X 2-PEG-PG进行反应连接的步骤，反应通式如下： Another aspect of the present invention provides a method for producing the above multi-arm single molecular weight polyethylene glycol, which comprises the compound of the present invention
Figure PCTCN2018093523-appb-000033
The step of reacting with WX 2 -PEG-PG, the reaction formula is as follows:

Figure PCTCN2018093523-appb-000034
Figure PCTCN2018093523-appb-000034

其中，所述A、X 1、Y、X 2、n、PEG具有本发明上述定义， Wherein A, X 1 , Y, X 2 , n, PEG have the above definition of the invention,

W为端基，选自：羟基、羧基、酯基、酮基、氨基、巯基、马来酰亚胺基、炔基和叠氮基中的一种，W is a terminal group selected from the group consisting of a hydroxyl group, a carboxyl group, an ester group, a ketone group, an amino group, a fluorenyl group, a maleimide group, an alkynyl group, and an azide group.

PG为羟基保护基团。PG is a hydroxy protecting group.

在本发明的一个实施例中，所述Y为羧基，W为氨基，或，所述Y为氨基，W为羧基。In one embodiment of the invention, Y is a carboxyl group, W is an amino group, or Y is an amino group and W is a carboxyl group.

在本发明的一个实施例中，所述Y为羟基，W为羧基，或，所述Y为羧基，W为羟基。In one embodiment of the invention, the Y is a hydroxyl group, W is a carboxyl group, or the Y is a carboxyl group and W is a hydroxyl group.

在本发明的一个实施例中，所述Y为酯基或酮基，W为氨基，或，所述Y为氨基，W为酯基或酮基。In one embodiment of the invention, Y is an ester or ketone group, W is an amino group, or Y is an amino group, and W is an ester group or a ketone group.

在本发明的一个实施例中，所述Y为马来酰亚胺基，W为巯基，或，所述Y为巯基，W为马来酰亚胺基。In one embodiment of the invention, the Y is a maleimide group, W is a fluorenyl group, or the Y is a fluorenyl group and W is a maleimide group.

在本发明的一个实施例中，所述Y为炔基，W为叠氮基，或，所述Y为叠氮基，W为炔基。In one embodiment of the invention, Y is an alkynyl group, W is an azide group, or Y is an azide group and W is an alkynyl group.

在本发明的一个实施例中，所述羟基保护基团包括但不限于：-CH 3、-C(CH 3) 3、-CH 2OCH 3、-COCH 3、-COC(CH 3) 3、-CH 2CH＝CH 2、-Si(CH 3) 3、

Figure PCTCN2018093523-appb-000035
但本领域技术人员可知，其他可实现羟基保护作用的基团也可用于上述制备反应，上述具体羟基保护基团并不用来限定本发明的保护范围。 In one embodiment of the invention, the hydroxy protecting group includes, but is not limited to: -CH 3 , -C(CH 3 ) 3 , -CH 2 OCH 3 , -COCH 3 , -COC(CH 3 ) 3 , -CH 2 CH=CH 2 , -Si(CH 3 ) 3 ,
Figure PCTCN2018093523-appb-000035
However, it will be understood by those skilled in the art that other groups which can achieve hydroxy protection can also be used in the above preparation reaction, and the above specific hydroxy protecting group is not intended to limit the scope of the present invention.

在本发明的一个实施例中，所述方法还包括羟基脱保护反应的步骤，反应通式如下：In one embodiment of the invention, the method further comprises the step of a hydroxyl deprotection reaction, the reaction formula being as follows:

Figure PCTCN2018093523-appb-000036
Figure PCTCN2018093523-appb-000036

本领域技术人员可知，现有技术中羟基脱保护的常规方法均可适用于上述反应，本发明对此不作具体限定。It is known to those skilled in the art that the conventional methods for deprotecting a hydroxyl group in the prior art can be applied to the above reaction, which is not specifically limited in the present invention.

本发明另一方面还提供一种上述多臂单一分子量聚乙二醇的活性衍生物，其具有如下结构：Another aspect of the present invention provides a living derivative of the above multi-arm single molecular weight polyethylene glycol having the following structure:

Figure PCTCN2018093523-appb-000037
Figure PCTCN2018093523-appb-000037

其中，所述A、X 1、R、X 2、n、PEG具有本发明上述定义， Wherein A, X 1 , R, X 2 , n, PEG have the above definition of the invention,

F为相同或不同的-X 3-Z型结构， F is the same or different -X 3 -Z structure,

X 3为连接基团，选自：-(CH 2) k-、-(CH 2) kO-、-(CH 2) kCO-、-(CH 2) kNH-、-(CH 2) kNHCO-、-(CH 2) kCONH-、-(CH 2) kNHCONH-、-(CH 2) kOCO-、-(CH 2) kCOO-、-(CH 2) kOCOO-和-(CH 2) kOCONH-中一种或两种以上的组合，k为0-10的整数， X 3 is a linking group selected from the group consisting of: -(CH 2 ) k -, -(CH 2 ) k O-, -(CH 2 ) k CO-, -(CH 2 ) k NH-, -(CH 2 ) k NHCO -, - (CH 2 ) k CONH -, - (CH 2) k NHCONH -, - (CH 2) k OCO -, - (CH 2) k COO -, - (CH 2) k OCOO- and - (CH 2 ) k OCONH- one or a combination of two or more, k is an integer from 0 to 10,

Z为活性端基，选自：-H、-NH 2、-ONH 2、-SH、-N 3、-Br、-CONH 2、-CONHNH 2、-COONH 2、-COOH、-PO 3H、-CHO、-CO-HA、-C≡CH、

Figure PCTCN2018093523-appb-000038
-COCH＝CH 2、-COC(CH 3)＝CH 2、-CN、-CH 2CH＝CH 2、-CH＝CH-COOH、-N＝C＝O、
Figure PCTCN2018093523-appb-000039
Figure PCTCN2018093523-appb-000040
Figure PCTCN2018093523-appb-000041
C1-6的烷基和C1-6的烷氧基中的一种， Z is a reactive end group selected from the group consisting of: -H, -NH 2 , -ONH 2 , -SH, -N 3 , -Br, -CONH 2 , -CONHNH 2 , -COONH 2 , -COOH, -PO 3 H, -CHO, -CO-HA, -C≡CH,
Figure PCTCN2018093523-appb-000038
-COCH=CH 2 , -COC(CH 3 )=CH 2 , -CN, -CH 2 CH=CH 2 , -CH=CH-COOH, -N=C=O,
Figure PCTCN2018093523-appb-000039
Figure PCTCN2018093523-appb-000040
Figure PCTCN2018093523-appb-000041
One of a C1-6 alkyl group and a C1-6 alkoxy group,

HA为卤原子(具体可为-F、-Cl、-Br或-I)，HA is a halogen atom (specifically -F, -Cl, -Br or -I),

E为C1-10烃基或含氟原子的C1-10的烃基，E is a C1-10 hydrocarbon group or a fluorine atom-containing C1-10 hydrocarbon group,

L 1-3为相同或不同的C1-10的烷基或C1-6的烷氧基。 L 1-3 is the same or different C1-10 alkyl group or C1-6 alkoxy group.

在本发明的一个实施例中，所述X 3中，所述k为1-5的整数，具体可为1、2、3、4或5，优选为1、2或3。 In an embodiment of the invention, in X 3 , the k is an integer from 1 to 5, specifically 1, 2, 3, 4 or 5, preferably 1, 2 or 3.

在本发明的一个优选实施例中，所述X 3选自：单键、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH 2O-、-CH 2CH 2O-、-CH 2CONHCH 2-和-CH 2CONHCH 2CH 2-中一种或两种以上的组合。 In a preferred embodiment of the invention, the X 3 is selected from the group consisting of: a single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 O-, -CH 2 One or a combination of two or more of CH 2 O-, -CH 2 CONHCH 2 -, and -CH 2 CONHCH 2 CH 2 -.

在本发明的一个优选实施例中，所述X 3为单键或-CH 2-。 In a preferred embodiment of the invention, said X 3 is a single bond or -CH 2 -.

在本发明的一个实施例中，所述Z选自：-H、-NH 2、-SH、-N 3、-Br、-CONH 2、-COOH、-CHO、-COCl、-COBr、-C≡CH、

Figure PCTCN2018093523-appb-000042
Figure PCTCN2018093523-appb-000043
Figure PCTCN2018093523-appb-000044
中的一种。 In one embodiment of the invention, the Z is selected from the group consisting of: -H, -NH 2 , -SH, -N 3 , -Br, -CONH 2 , -COOH, -CHO, -COCl, -COBr, -C ≡CH,
Figure PCTCN2018093523-appb-000042
Figure PCTCN2018093523-appb-000043
Figure PCTCN2018093523-appb-000044
One of them.

在本发明的一个实施例中，所述活性衍生物中，所述F为

Figure PCTCN2018093523-appb-000045
In one embodiment of the invention, in the active derivative, the F is
Figure PCTCN2018093523-appb-000045

在本发明另一个实施例中，所述活性衍生物中，所述F包括-H和-CH 2COOH。 In yet another embodiment of the invention, the active derivative, including the F -H and -CH 2 COOH.

在本发明的一个实施例中，所述多臂单一分子量聚乙二醇活性衍生物具有如下结构：In one embodiment of the invention, the multi-arm single molecular weight polyethylene glycol reactive derivative has the structure:

Figure PCTCN2018093523-appb-000046
Figure PCTCN2018093523-appb-000046

F 11-14为相同或不同的-X 3-Z型结构。 F 11-14 is the same or different -X 3 -Z type structure.

在本发明的一个实施例中，式Ⅴ-1中，m为4。In one embodiment of the invention, in the formula V-1, m is 4.

在本发明的一个实施例中，式Ⅴ-1中，m为12。In one embodiment of the invention, in the formula V-1, m is 12.

在本发明的一个实施例中，式Ⅴ-1中，m为24。In one embodiment of the invention, in the formula V-1, m is 24.

在本发明的一个实施例中，式Ⅴ-1中，F 11-14均为

Figure PCTCN2018093523-appb-000047
In an embodiment of the invention, in the formula V-1, F 11-14 are
Figure PCTCN2018093523-appb-000047

在本发明的一个实施例中，式Ⅴ-1中，F 11-14中包括-H和-CH 2COOH。 In one embodiment of the present invention, in Formula Ⅴ-1, F 11-14 includes -H and -CH 2 COOH.

在本发明的一个优选实施例中，式Ⅴ-1中，F 11-13均为-H，F 14为-CH 2COOH。 In a preferred embodiment of the invention, in Formula V-1, F 11-13 is both -H and F 14 is -CH 2 COOH.

在本发明的另一个优选实施例中，式Ⅴ-1中，F 11和F 12为-H，F 13和F 14为-CH 2COOH。 In another preferred embodiment of the invention, in Formula V-1, F 11 and F 12 are -H, and F 13 and F 14 are -CH 2 COOH.

在本发明的一个实施例中，式Ⅴ-1中，F 11-14中包括-H和-NH 2。 In one embodiment of the present invention, in Formula Ⅴ-1, F 11-14 includes -H and -NH 2.

在本发明的一个优选实施例中，式Ⅴ-1中，F 11-13均为-H，F 14为-NH 2。 In a preferred embodiment of the invention, in Formula V-1, F 11-13 is both -H and F 14 is -NH 2 .

在本发明的另一个优选实施例中，式Ⅴ-1中，F 11和F 12为-H，F 13和F 14为-NH 2。 In another preferred embodiment of the invention, in Formula V-1, F 11 and F 12 are -H, and F 13 and F 14 are -NH 2 .

在本发明的一个更优选实施例中，式Ⅴ-1中，m为12，F 11-14均为

Figure PCTCN2018093523-appb-000048
In a more preferred embodiment of the invention, in the formula V-1, m is 12 and F 11-14 are
Figure PCTCN2018093523-appb-000048

在本发明的另一个更优选实施例中，式Ⅴ-1中，m为24，F 11-14均为

Figure PCTCN2018093523-appb-000049
In another more preferred embodiment of the present invention, in the formula V-1, m is 24 and F 11-14 are
Figure PCTCN2018093523-appb-000049

在本发明的另一个更优选实施例中，式Ⅴ-1中，m为24，F 11-13均为-H，F 14为-CH 2COOH。 In another more preferred embodiment of the present invention, in the formula V-1, m is 24, F 11-13 is -H, and F 14 is -CH 2 COOH.

在本发明的另一个更优选实施例中，式Ⅴ-1中，m为24，F 11和F 12为-H，F 13和F 14为-CH 2COOH。 In another more preferred embodiment of the invention, in Formula V-1, m is 24, F 11 and F 12 are -H, and F 13 and F 14 are -CH 2 COOH.

在本发明的一个实施例中，所述多臂单一分子量聚乙二醇活性衍生物具有如下结构：In one embodiment of the invention, the multi-arm single molecular weight polyethylene glycol reactive derivative has the structure:

Figure PCTCN2018093523-appb-000050
Figure PCTCN2018093523-appb-000050

F 21-26为相同或不同的-X 3-Z型结构。 F 21-26 is the same or different -X 3 -Z type structure.

在本发明的一个实施例中，式Ⅴ-2中，m为4。In one embodiment of the invention, in the formula V-2, m is 4.

在本发明的一个实施例中，式Ⅴ-2中，m为12。In one embodiment of the invention, in the formula V-2, m is 12.

在本发明的一个实施例中，式Ⅴ-2中，m为24。在本发明的一个实施例中，式Ⅴ-2中，F 21-26均为

Figure PCTCN2018093523-appb-000051
In one embodiment of the invention, in formula V-2, m is 24. In an embodiment of the invention, in the formula V-2, F 21-26 are
Figure PCTCN2018093523-appb-000051

在本发明的一个实施例中，式Ⅴ-2中，F 21-26中包括-H和-CH 2COOH。 In one embodiment of the present invention, in Formula Ⅴ-2, F 21-26 includes -H and -CH 2 COOH.

在本发明的一个实施例中，式Ⅴ-2中，F 21-25均为-H，F 26为-CH 2COOH。 In one embodiment of the invention, in Formula V-2, F 21-25 is both -H and F 26 is -CH 2 COOH.

在本发明的一个实施例中，式Ⅴ-2中，F 21-26中包括-H和-NH 2。 In one embodiment of the present invention, in Formula Ⅴ-2, F 21-26 includes -H and -NH 2.

在本发明的一个实施例中，式Ⅴ-2中，F 21-25均为-H，F 26为-NH 2。 In one embodiment of the invention, in Formula V-2, F 21-25 is both -H and F 26 is -NH 2 .

在本发明的一个实施例中，所述多臂单一分子量聚乙二醇活性衍生物具有如下结构：In one embodiment of the invention, the multi-arm single molecular weight polyethylene glycol reactive derivative has the structure:

Figure PCTCN2018093523-appb-000052
Figure PCTCN2018093523-appb-000052

F 31-38为相同或不同的-X 3-Z型结构。 F 31-38 are the same or different -X 3 -Z type structures.

在本发明的一个实施例中，式Ⅴ-3中，m为4。In one embodiment of the invention, in the formula V-3, m is 4.

在本发明的一个实施例中，式Ⅴ-3中，m为12。In one embodiment of the invention, in formula V-3, m is 12.

在本发明的一个实施例中，式Ⅴ-3中，m为24。In one embodiment of the invention, in the formula V-3, m is 24.

在本发明的一个实施例中，式Ⅴ-3中，F 31-38均为

Figure PCTCN2018093523-appb-000053
In an embodiment of the invention, in the formula V-3, F 31-38 are
Figure PCTCN2018093523-appb-000053

在本发明的一个实施例中，式Ⅴ-3中，F 31-38中包括-H和-CH 2COOH。 In one embodiment of the present invention, in formula Ⅴ-3, F 31-38 includes -H and -CH 2 COOH.

在本发明的一个实施例中，式Ⅴ-3中，F 31-37均为-H，F 38为-CH 2COOH。 In one embodiment of the invention, in Formula V-3, F 31-37 are both -H and F 38 is -CH 2 COOH.

在本发明的一个实施例中，式Ⅴ-3中，F 31-38中包括-H和-NH 2。 In one embodiment of the present invention, in Formula V-3, -H and -NH 2 are included in F 31-38 .

在本发明的一个实施例中，式Ⅴ-3中，F 31-37均为-H，F 38为-NH 2。 In one embodiment of the invention, in Formula V-3, F 31-37 are both -H and F 38 is -NH 2 .

在本发明的一个实施例中，所述多臂单一分子量聚乙二醇活性衍生物具有如下结构：In one embodiment of the invention, the multi-arm single molecular weight polyethylene glycol reactive derivative has the structure:

Figure PCTCN2018093523-appb-000054
Figure PCTCN2018093523-appb-000054

F 41-48为相同或不同的-X 3-Z型结构。 F 41-48 are the same or different -X 3 -Z type structures.

在本发明的一个实施例中，式Ⅴ-4中，m为4。In one embodiment of the invention, in the formula V-4, m is 4.

在本发明的一个实施例中，式Ⅴ-4中，m为12。In one embodiment of the invention, in formula V-4, m is 12.

在本发明的一个实施例中，式Ⅴ-4中，m为24。In one embodiment of the invention, in formula V-4, m is 24.

在本发明的一个实施例中，式Ⅴ-4中，F 41-48均为

Figure PCTCN2018093523-appb-000055
In an embodiment of the invention, in the formula V-4, F 41-48 are
Figure PCTCN2018093523-appb-000055

在本发明的一个实施例中，式Ⅴ-4中，F 41-48中包括-H和-CH 2COOH。 In one embodiment of the present invention, in Formula Ⅴ-4, F 41-48 includes -H and -CH 2 COOH.

在本发明的一个实施例中，式Ⅴ-4中，F 41-47均为-H，F 48为-CH 2COOH。 In one embodiment of the invention, in Formula V-4, F 41-47 are both -H and F 48 is -CH 2 COOH.

在本发明的一个实施例中，式Ⅴ-4中，F 41-48中包括-H和-NH 2。 In one embodiment of the invention, in Formula V-4, -H and -NH 2 are included in F 41-48 .

在本发明的一个实施例中，式Ⅴ-4中，F F 41-47均为-H，F 48为-NH 2。 In one embodiment of the invention, in Formula V-4, F F 41-47 are both -H and F 48 is -NH 2 .

在本发明的一个实施例中，所述多臂单一分子量聚乙二醇活性衍生物具有如下结构：In one embodiment of the invention, the multi-arm single molecular weight polyethylene glycol reactive derivative has the structure:

Figure PCTCN2018093523-appb-000056
Figure PCTCN2018093523-appb-000056

F 51-53为相同或不同的-X 3-Z型结构。 F 51-53 is the same or different -X 3 -Z type structure.

在本发明的一个实施例中，式Ⅴ-5中，m为4。In one embodiment of the invention, in Formula V-5, m is 4.

在本发明的一个实施例中，式Ⅴ-5中，m为12。In one embodiment of the invention, in formula V-5, m is 12.

在本发明的一个实施例中，式Ⅴ-5中，m为24。In one embodiment of the invention, in formula V-5, m is 24.

在本发明的一个实施例中，式Ⅴ-5中，F 51-53均为

Figure PCTCN2018093523-appb-000057
In an embodiment of the invention, in the formula V-5, F 51-53 are
Figure PCTCN2018093523-appb-000057

在本发明的一个实施例中，所述多臂单一分子量聚乙二醇活性衍生物具有如下结构：In one embodiment of the invention, the multi-arm single molecular weight polyethylene glycol reactive derivative has the structure:

Figure PCTCN2018093523-appb-000058
Figure PCTCN2018093523-appb-000058

F 61-64为相同或不同的-X 3-Z型结构。 F 61-64 are the same or different -X 3 -Z type structures.

在本发明的一个实施例中，式Ⅴ-6中，m为4。In one embodiment of the invention, in Formula V-6, m is 4.

在本发明的一个实施例中，式Ⅴ-6中，m为12。In one embodiment of the invention, in formula V-6, m is 12.

在本发明的一个实施例中，式Ⅴ-6中，m为24。In one embodiment of the invention, in formula V-6, m is 24.

在本发明的一个实施例中，式Ⅴ-6中，F 61-64均为

Figure PCTCN2018093523-appb-000059
In an embodiment of the invention, in the formula V-6, F 61-64 are
Figure PCTCN2018093523-appb-000059

本发明另一方面还提供一种上述多臂单一分子量聚乙二醇活性衍生物形成的凝胶。Another aspect of the invention also provides a gel formed from the above multi-arm single molecular weight polyethylene glycol active derivative.

本发明另一方面还提供一种上述多臂单一分子量聚乙二醇与药物分子的结合物。Another aspect of the present invention also provides a combination of the above multi-arm single molecular weight polyethylene glycol and a drug molecule.

本发明另一方面还提供一种上述多臂单一分子量聚乙二醇活性衍生物与药物分子的结合物。Another aspect of the present invention also provides a combination of the above multi-arm single molecular weight polyethylene glycol active derivative and a drug molecule.

在本发明的一个实施例中，所述药物分子选自以下药物分子组成的组：氨基酸、多肽、蛋白质、核苷、糖类、有机酸、黄酮类、醌类、萜类、苯丙素酚类、甾体及其苷类和生物碱类药物及其组合。In one embodiment of the invention, the drug molecule is selected from the group consisting of amino acids, polypeptides, proteins, nucleosides, sugars, organic acids, flavonoids, terpenoids, terpenoids, phenylpropanol Classes, steroids and their glycosides and alkaloids and combinations thereof.

在本发明的一个具体实施方式中，所述的药物分子选自：苯丁酸氮芥、顺铂、5-氟脲嘧啶、紫杉醇、阿霉素、甲氨蝶呤、依诺替康和多西紫杉醇中一种或多种。In a specific embodiment of the invention, the drug molecule is selected from the group consisting of: chlorambucil, cisplatin, 5-fluorouracil, paclitaxel, doxorubicin, methotrexate, ennotecan and more One or more of the paclitaxel.

在本发明的另一个具体实施方式中，所述的药物分子选自：干扰素、白介素、肿瘤坏死因子、生长因子、集落刺激因子、促红细胞生成素和超氧化物歧化酶中的一种或多种。In another embodiment of the present invention, the drug molecule is selected from the group consisting of: interferon, interleukin, tumor necrosis factor, growth factor, colony stimulating factor, erythropoietin, and superoxide dismutase A variety.

在本发明的一个优选实施例中，所述的药物分子为多西紫杉醇。In a preferred embodiment of the invention, the drug molecule is docetaxel.

在本发明的一个优选实施例中，所述的药物分子为依诺替康。In a preferred embodiment of the invention, the drug molecule is INOTEC.

在本发明的一个优选实施例中，所述多臂单一分子量聚乙二醇活性衍生物为八臂聚乙二醇乙酸。In a preferred embodiment of the invention, the multi-arm single molecular weight polyethylene glycol reactive derivative is an eight-arm polyethylene glycol acetate.

在本发明的一个更优选实施例中，本发明所述的结合物为八臂聚乙二醇乙酸与依诺替康或多西紫杉醇形成的结合物。In a more preferred embodiment of the invention, the combination of the invention is a combination of eight-arm polyethylene glycol acetate with enonotecan or docetaxel.

本发明的另一方面还提供一种包含上述结合物与药学上可接受的添加剂的药物组合物。Another aspect of the invention also provides a pharmaceutical composition comprising the above conjugate and a pharmaceutically acceptable additive.

所述的药物组合物中，所述添加剂可为赋形剂、崩解剂、粘结剂、润滑剂、悬浮剂、稳定剂、填充剂和粘合剂等等中的任一种或多种。赋形剂的例子包括乳糖、甘露醇、益寿糖、微晶纤维素、硅化微晶纤维素和粉状纤维素等等；崩解剂的例子包括低取代羟丙基纤维素、交聚维酮、羧基乙酸淀粉钠、交联羧甲基纤维素钠和淀粉等等；粘结剂的例子包括羟丙基纤维素、羟丙甲纤维素、聚维酮、共聚维酮和预胶凝淀粉等等；润滑剂的例子包括硬脂酸、硬脂酸镁和富马酰硬脂酸钠等等；润湿剂的例子包括聚氧乙烯山梨糖醇酐脂肪酸酯、泊洛沙姆和聚氧乙烯蓖麻油衍生物等等；悬浮剂的例子包括羟丙甲纤维素、羟丙基纤维素、聚维酮、共聚维酮、羧甲基纤维素钠和甲基纤维素等等；稳定剂的例子包括柠檬酸、富马酸和琥珀酸等等；填充剂的例子包括淀粉、蔗糖、乳糖和微晶纤维素等；粘合剂的例子包括纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮等。另外，本发明的药物组合物还可包括阻凝剂、增味剂、乳化剂和防腐剂等等中的任一种或多种。In the pharmaceutical composition, the additive may be any one or more of an excipient, a disintegrant, a binder, a lubricant, a suspending agent, a stabilizer, a filler, a binder, and the like. . Examples of the excipient include lactose, mannitol, isomalt, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, and the like; examples of the disintegrator include low-substituted hydroxypropylcellulose, cross-linked vitamins Ketones, sodium starch glycolate, croscarmellose sodium, starch, etc.; examples of binders include hydroxypropylcellulose, hypromellose, povidone, copovidone and pregelatinized starch Etc. Examples of the lubricant include stearic acid, magnesium stearate, and sodium fumarate, and the like; examples of the wetting agent include polyoxyethylene sorbitan fatty acid ester, poloxamer, and poly Oxyethylene castor oil derivatives and the like; examples of suspending agents include hypromellose, hydroxypropylcellulose, povidone, copovidone, sodium carboxymethylcellulose, methylcellulose, and the like; stabilizers Examples include citric acid, fumaric acid, succinic acid and the like; examples of the filler include starch, sucrose, lactose, and microcrystalline cellulose; and examples of the binder include cellulose derivatives, alginate, gelatin, and poly Vinyl pyrrolidone and the like. Further, the pharmaceutical composition of the present invention may further include any one or more of an anti-coagulant, a flavor enhancer, an emulsifier, a preservative, and the like.

本发明所述的药物组合物可以为片剂(包括糖衣片剂、膜包衣片剂、舌下片剂、口腔崩解片和口腔片剂等等)、丸剂、粉剂、颗粒剂、胶囊剂(包括软胶囊和微胶囊等)、锭剂、糖浆剂、液体、乳剂、混悬剂、控制释放制剂(例如，瞬时释放制剂、缓释制剂和缓释微囊)、气雾剂、膜剂(例如，口服崩解膜剂、口腔粘膜-粘附膜剂)、注射剂(例如，皮下注射、静脉注射、肌内注射和腹膜内注射)、静脉滴注剂、透皮吸收制剂、软膏剂、洗剂、粘附制剂、栓剂(例如，直肠栓剂和阴道栓剂等)、小药丸、鼻制剂、肺制剂(吸入剂)、眼睛滴剂等等、口服或胃肠外制剂(例如，静脉内、肌内、皮下、器官内、鼻内、皮内、滴注、脑内和直肠内等给药形式，给药至肿瘤的附近和直接给药至病变处)。The pharmaceutical composition of the present invention may be a tablet (including a sugar-coated tablet, a film-coated tablet, a sublingual tablet, an orally disintegrating tablet, an oral tablet, etc.), a pill, a powder, a granule, a capsule. (including soft capsules and microcapsules, etc.), lozenges, syrups, liquids, emulsions, suspensions, controlled release preparations (for example, transient release preparations, sustained release preparations and sustained release microcapsules), aerosols, films (for example, an oral disintegrating film, an oral mucosa-adhesive film), an injection (for example, subcutaneous injection, intravenous injection, intramuscular injection, and intraperitoneal injection), an intravenous drip, a transdermal absorption preparation, an ointment, Lotions, adhesive preparations, suppositories (eg, rectal suppositories and pessaries, etc.), small pills, nasal preparations, pulmonary preparations (inhalation), eye drops, etc., oral or parenteral preparations (eg, intravenous, Administration forms such as intramuscular, subcutaneous, intra-organ, intranasal, intradermal, instillation, intracerebral and rectal administration, administration to the vicinity of the tumor and direct administration to the lesion).

本发明另一方面还提供一种上述化合物在制备多臂聚乙二醇、多臂聚乙二醇活性衍生物及其药物结合物、药物组合物中的应用。Another aspect of the present invention also provides the use of the above compound in the preparation of a multi-arm polyethylene glycol, a multi-arm polyethylene glycol active derivative, and a pharmaceutical combination thereof, and a pharmaceutical composition.

在本发明的一个实施例中，所述多臂聚乙二醇为本发明上述多臂单一分子量聚乙二醇。In one embodiment of the invention, the multi-arm polyethylene glycol is the multi-arm single molecular weight polyethylene glycol of the invention described above.

在本发明的一个实施例中，所述多臂聚乙二醇活性衍生物为本发明上述多臂单一分子量聚乙二醇活性衍生物。In one embodiment of the invention, the multi-arm polyethylene glycol reactive derivative is the above-described multi-arm single molecular weight polyethylene glycol active derivative of the invention.

本发明另一方面还提供一种上述多臂单一分子量聚乙二醇在制备多臂聚乙二醇活性衍生物及其药物结合物、药物组合物中的应用。Another aspect of the present invention provides a use of the above multi-arm single molecular weight polyethylene glycol in the preparation of a multi-arm polyethylene glycol active derivative, a pharmaceutical combination thereof, and a pharmaceutical composition.

本发明另一方面还提供一种上述多臂单一分子量聚乙二醇活性衍生物在制备凝胶、药物结合物和药物组合物中的应用。Another aspect of the present invention also provides the use of the above multi-arm single molecular weight polyethylene glycol active derivative for the preparation of gels, drug conjugates and pharmaceutical compositions.

本发明另一方面还提供一种上述凝胶在制备药物载体和医疗器械产品中的应用。Another aspect of the invention also provides the use of the above gel in the preparation of a pharmaceutical carrier and a medical device product.

在本发明的一个实施例中，所述医疗器械产品选自：粘合剂、防渗透剂、防粘连剂和止血材料等的一种或多种。In one embodiment of the invention, the medical device product is selected from one or more of the group consisting of: a binder, a barrier agent, an anti-blocking agent, and a hemostatic material.

本发明另一方面还提供一种上述多臂单一分子量聚乙二醇、多臂单一分子量聚乙二醇活性衍生物，及其药物结合物、药物组合物、凝胶在制备预防和/或治疗疾病的药物中的应用。Another aspect of the present invention provides a multi-arm single molecular weight polyethylene glycol, a multi-arm single molecular weight polyethylene glycol active derivative, and a pharmaceutical combination thereof, a pharmaceutical composition, a gel, and a preparation for prevention and/or treatment. The application of drugs for diseases.

本发明提供的多臂单一分子量聚乙二醇及其活性衍生物为单一分子量的化合物，避免了原有技术中高分子聚合物混合物的应用，有效提高了药物的纯度。多臂单一分子量聚乙二醇及其活性衍生物用于药物修饰，可有效改善药物的溶解性、稳定性和免疫原性，改善药物的体内吸收，延长药物的半衰期，可提高药物的生物利用度，增强疗效，降低毒副作用。本发明提供的多臂单一分子量聚乙二醇活性衍生物形成的凝胶可用于制备缓控释药物，延长药物作用时间，减少给药次数，提高病人依从性。The multi-arm single molecular weight polyethylene glycol and the reactive derivative thereof provided by the invention are single molecular weight compounds, avoiding the application of the high molecular polymer mixture in the prior art, and effectively improving the purity of the drug. The multi-arm single molecular weight polyethylene glycol and its active derivative are used for drug modification, which can effectively improve the solubility, stability and immunogenicity of the drug, improve the absorption of the drug in vivo, prolong the half-life of the drug, and improve the bioavailability of the drug. Degree, enhance efficacy, reduce toxic side effects. The gel formed by the multi-arm single molecular weight polyethylene glycol active derivative provided by the invention can be used for preparing a controlled release drug, prolonging the action time of the drug, reducing the number of administrations, and improving patient compliance.

具体实施方式Detailed ways

本发明中，术语“保护基团”是指通常用于在化合物的其他官能团发生反应时阻止或保护具体官能团的取代基。例如，“羟基保护基团”是指与羟基相连的阻止或保护羟基官能团的取代基，常用的羟基保护基团包括乙酰基、三烷基甲硅烷基等。针对保护基团的一般描述及其用途，参见T.W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991。In the present invention, the term "protecting group" means a substituent which is generally used to prevent or protect a specific functional group when other functional groups of the compound react. For example, "hydroxy protecting group" refers to a substituent attached to a hydroxyl group that blocks or protects a hydroxyl functional group. Commonly used hydroxyl protecting groups include an acetyl group, a trialkylsilyl group, and the like. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

术语“药学上可接受”是指在对人施用后具有生理相容性并且不会引起肠胃失调、诸如头晕的过敏反应或类似反应。The term "pharmaceutically acceptable" refers to an allergic reaction or the like which is physiologically compatible after administration to a human and does not cause gastrointestinal disorders such as dizziness.

术语“预防”或“治疗”包括治疗性或预防性处理或措施，目标是预防或减慢靶向的病理性状况或病症。如果根据本发明的方法接收治疗量的本发明所述融合蛋白后，对象表现出可观察和/或可测量的特定疾病一个或多个体征和症状的减少或消失，则该对象被成功“预防”或“治疗”。The term "prevention" or "treatment" includes therapeutic or prophylactic treatment or measures with the goal of preventing or slowing down a targeted pathological condition or disorder. A subject is successfully "prevented" if, after receiving a therapeutic amount of the fusion protein of the invention according to the method of the invention, the subject exhibits a decrease or disappearance of one or more signs and symptoms of a particular disease that is observable and/or measurable "or "treatment."

下面将结合本发明实施例，对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。The technical solutions of the present invention will be described clearly and completely in conjunction with the embodiments of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative efforts are within the scope of the present invention.

本发明所用的化合物可以商购，也可以根据公开的制备方法进行制备，其并不限制本发明的治疗范围。The compounds used in the present invention are either commercially available or can be prepared according to the disclosed preparation methods, which do not limit the therapeutic range of the present invention.

实施例1：四丙烯酸取代季戊四醇的合成Example 1: Synthesis of tetraacrylic acid substituted pentaerythritol

合成如下结构的四丙烯酸取代季戊四醇(Ia)：Synthesis of tetraacrylic acid substituted pentaerythritol (Ia) having the following structure:

Figure PCTCN2018093523-appb-000060
Figure PCTCN2018093523-appb-000060

向三口瓶中加入季戊四醇(1mol)、叔丁醇钾(0.01mol)、DMF，搅拌，然后称取丙烯酸叔丁酯(5mol)滴加入反应液室温反应过夜。反应完后过滤，旋干反应液，硅胶柱柱分可得到四丙烯酸叔丁酯取代季戊四醇纯品。Pentaerythritol (1 mol), potassium t-butoxide (0.01 mol), and DMF were added to a three-necked flask, and the mixture was stirred. Then, tert-butyl acrylate (5 mol) was added dropwise to the reaction solution to react at room temperature overnight. After the completion of the reaction, the mixture was filtered, and the reaction mixture was evaporated to dryness, and a silica gel column was used to obtain a crude product of tert-butyl tetraacrylate instead of pentaerythritol.

将四丙烯酸叔丁酯取代季戊四醇纯品溶于含50％TFA的二氯甲烷溶液中，室温反应过夜。反应结束后旋干反应液，乙腈重结晶可以得到四丙烯酸取代季戊四醇纯品。The tert-butyl tetraacrylate substituted pentaerythritol was dissolved in a dichloromethane solution containing 50% TFA and allowed to react at room temperature overnight. After the completion of the reaction, the reaction solution was spin-dried, and acetonitrile was recrystallized to obtain a pure tetrakis acid-substituted pentaerythritol.

1H-NMR(DMSO-d 6)：2.32-2.36(t，8H)，3.20(s，8H)，3.50-3.54(t，8H)。 1 H-NMR (DMSO-d 6 ): 2.32 - 2.36 (t, 8H), 3.20 (s, 8H), 3.50 - 3.54 (t, 8H).

实施例2：八丙烯酸取代季戊四醇四甘油醚的合成Example 2: Synthesis of octaacrylic acid substituted pentaerythritol tetraglyceride

合成如下结构的八丙烯酸取代季戊四醇四甘油醚(Ib)：The octaacrylic acid substituted pentaerythritol tetraglyceride (Ib) having the following structure was synthesized:

Figure PCTCN2018093523-appb-000061
Figure PCTCN2018093523-appb-000061

向三口瓶中加入季戊四醇四甘油醚(1mol)、叔丁醇钾(0.01mol)、DMF，搅拌，然后称取丙烯酸叔丁酯(10mol)滴加入反应液室温反应过夜。反应完后过滤，旋干反应液，硅胶柱柱分可得到八丙烯酸叔丁酯取代季戊四醇甘油醚纯品。Pentaerythritol tetraglyceride (1 mol), potassium t-butoxide (0.01 mol), and DMF were added to a three-necked flask, and the mixture was stirred. Then, tert-butyl acrylate (10 mol) was added dropwise to the reaction solution to react at room temperature overnight. After the completion of the reaction, the mixture was filtered, and the reaction mixture was evaporated to dryness, and a column of silica gel column was used to obtain a pure product of tert-butyl octaacrylate and pentaerythritol glycerol ether.

将八丙烯酸叔丁酯取代季戊四醇甘油醚纯品溶于含50％TFA的二氯甲烷溶液中，室温反应过夜。反应结束后旋干反应液，乙腈重结晶可以得到八丙烯酸取代季戊四醇甘油醚纯品。The pure tert-butyl octaacrylate substituted pentaerythritol glyceryl ether was dissolved in a dichloromethane solution containing 50% TFA and allowed to react at room temperature overnight. After the completion of the reaction, the reaction solution was spin-dried, and acetonitrile was recrystallized to obtain a pure product of octaacrylic acid substituted pentaerythritol glyceryl ether.

1H-NMR(DMSO-d 6)：2.39-2.45(m，16H)，3.29-3.40(m，24H)，3.51-3.55(m，4H)，3.57-3.61(m，8H)，3.67-3.72(m，8H)； 1 H-NMR (DMSO-d 6 ): 2.39-2.45 (m, 16H), 3.29-3.40 (m, 24H), 3.51-3.55 (m, 4H), 3.57-3.61 (m, 8H), 3.67-3.72 (m, 8H);

MALDI-TOF(1031.0，M+Na)。MALDI-TOF (1031.0, M+Na).

实施例3：4ARM-(EG 24-OH) 4的合成 Example 3: Synthesis of 4ARM-(EG 24 -OH) 4

合成如下结构的4ARM-(EG 24-OH) 4(IIa)： The following structure was synthesized for 4ARM-(EG 24 -OH) 4 (IIa):

Figure PCTCN2018093523-appb-000062
Figure PCTCN2018093523-appb-000062

向三口瓶中加入四丙烯酸取代季戊四醇(Ia，1mol，实施例1制备)和NHS(4.4mol)，然后用DMF搅拌溶解，加入DCC(5.2mol)室温反应过夜得到反应液一；然后，称取NH 2(CH 2CH 2O) 24Tr(4.8mol)和三乙胺(5.2mol)溶于DMF中得到反应液二；最后，将反应液一滴加到反应液二中，室温反应24小时结束反应。反应完后，过滤、旋干滤液，再经硅胶柱纯化得到4ARM-(EG 24-OTr) 4纯品。 To the three-necked bottle, tetrakis acid-substituted pentaerythritol (Ia, 1 mol, prepared in Example 1) and NHS (4.4 mol) were added, and then dissolved by stirring with DMF, and DCC (5.2 mol) was added thereto to react at room temperature overnight to obtain a reaction liquid 1; NH 2 (CH 2 CH 2 O) 24 Tr (4.8 mol) and triethylamine (5.2 mol) were dissolved in DMF to obtain a reaction liquid 2; finally, a drop of the reaction solution was added to the reaction liquid 2, and the reaction was terminated at room temperature for 24 hours. reaction. After the reaction, the filtrate was filtered, and the filtrate was dried, and then purified through silica gel column to obtain 4 ARM-(EG 24 -OTr) 4 pure product.

将4ARM-(EG 24-OTr) 4纯品溶于8％TFA的二氯甲烷溶液中，室温反应过夜，冰浴条件下加入适量0.1g/ml的氢氧化钠溶液，然后再室温反应3小时。反应结束后用1N盐酸调反应液pH值到6.5-7，然后加入适量氯化钠，二氯甲烷萃取两次，并旋干二氯甲烷相，然后加入适量水溶解二氯甲烷相旋干物，再过滤收集滤液，旋干滤液即得产品4ARM-(EG 24-OH) 4。 The 4ARM-(EG 24 -OTr) 4 pure product was dissolved in 8% TFA in dichloromethane, and reacted at room temperature overnight, and an appropriate amount of 0.1 g/ml sodium hydroxide solution was added under ice bath, and then reacted at room temperature for 3 hours. . After the reaction, the pH of the reaction solution was adjusted to 6.5-7 with 1N hydrochloric acid, then the appropriate amount of sodium chloride was added, and the mixture was extracted twice with dichloromethane, and the dichloromethane phase was spun, and then the appropriate amount of water was added to dissolve the dichloromethane. The filtrate was again collected by filtration, and the filtrate was dried to give the product 4ARM-(EG 24 -OH) 4 .

1H-NMR(DMSO-d 6)：2.26-2.30(m，8H)，3.17-3.21(m，16H)，3.35-3.64(m，384H)，4.58-4.62(t，4H)，7.90-7.94(t，4H)； 1 H-NMR (DMSO-d 6 ): 2.26-2.30 (m, 8H), 3.17-3.21 (m, 16H), 3.35-3.64 (m, 384H), 4.58-4.62 (t, 4H), 7.90-7.94 (t, 4H);

MALDI-TOF(4671.5，M+Na)。MALDI-TOF (4671.5, M+Na).

实施例4：4ARM-(EG 12-OH) 4的合成 Example 4: Synthesis of 4ARM-(EG 12 -OH) 4

合成如下结构的4ARM-(EG 12-OH) 4(IIb)： The following structure was synthesized for 4ARM-(EG 12 -OH) 4 (IIb):

Figure PCTCN2018093523-appb-000063
Figure PCTCN2018093523-appb-000063

向三口瓶中加入四丙烯酸取代季戊四醇(Ia，1mol，实施例1制备)和NHS(4.4mol)，然后用DMF搅拌溶解，加入DCC(5.2mol)室温反应过夜得到反应液一；然后，称取NH 2(CH 2CH 2O) 12Tr(4.8mol)和三乙胺(5.2mol)溶于DMF中得到反应液二；最后，将反应液一滴加到反应液二中，室温反应24小时结束反应。反应完后，过滤、旋干滤液，再经硅胶柱纯化得到4ARM-(EG 12-OTr) 4纯品。 To the three-necked bottle, tetrakis acid-substituted pentaerythritol (Ia, 1 mol, prepared in Example 1) and NHS (4.4 mol) were added, and then dissolved by stirring with DMF, and DCC (5.2 mol) was added thereto to react at room temperature overnight to obtain a reaction liquid 1; NH 2 (CH 2 CH 2 O) 12 Tr (4.8 mol) and triethylamine (5.2 mol) were dissolved in DMF to obtain a reaction liquid 2; finally, a drop of the reaction liquid was added to the reaction liquid 2, and the reaction was completed at room temperature for 24 hours. reaction. After the reaction, the filtrate was filtered, and the filtrate was dried, and then purified through silica gel column to obtain 4ARM-(EG 12 -OTr) 4 pure product.

将4ARM-(EG 12-OTr) 4纯品溶于8％TFA的二氯甲烷溶液中，室温反应过夜，冰浴条件下加入适量0.1g/ml的氢氧化钠溶液，然后再室温反应3小时。反应结束后用1N盐酸调反应液pH值到6.5-7，然后加入适量氯化钠，二氯甲烷萃取两次，并旋干二氯甲烷相，然后加入适量水溶解二氯甲烷相旋干物，再过滤收集滤液，旋干滤液即得产品4ARM-(EG 12-OH) 4。 The 4ARM-(EG 12 -OTr) 4 pure product was dissolved in 8% TFA in dichloromethane, and reacted at room temperature overnight, and an appropriate amount of 0.1 g/ml sodium hydroxide solution was added under ice bath, and then reacted at room temperature for 3 hours. . After the reaction, the pH of the reaction solution was adjusted to 6.5-7 with 1N hydrochloric acid, then the appropriate amount of sodium chloride was added, and the mixture was extracted twice with dichloromethane, and the dichloromethane phase was spun, and then the appropriate amount of water was added to dissolve the dichloromethane. The filtrate was again collected by filtration, and the filtrate was dried to give the product 4ARM-(EG 12 - OH) 4 .

1H-NMR(DMSO-d 6)：2.26-2.30(m，8H)，3.17-3.21(m，16H)，3.35-3.64(m，192H)，4.56-4.59(t，4H)，7.88-7.92(t，4H)； 1 H-NMR (DMSO-d 6 ): 2.26-2.30 (m, 8H), 3.17-3.21 (m, 16H), 3.35-3.64 (m, 192H), 4.56-4.59 (t, 4H), 7.88-7.92 (t, 4H);

MALDI-TOF(2557.6，M+Na)。MALDI-TOF (2557.6, M+Na).

实施例5：8ARM-(EG 4-OH) 8的合成 Example 5: Synthesis of 8ARM-(EG 4 -OH) 8

合成如下结构的8ARM-(EG 4-OH) 8(IIc)： The following structure was synthesized for 8ARM-(EG 4 -OH) 8 (IIc):

Figure PCTCN2018093523-appb-000064
Figure PCTCN2018093523-appb-000064

向三口瓶中加入八丙烯酸取代季戊四醇四甘油醚(Ib，1mol，实施例2制备)和NHS(8.8mol)，然后用DMF搅拌溶解，加入DCC(10.4mol)室温反应过夜得到反应液一；然后，称取NH 2(CH 2CH 2O) 4Tr(9.6mol)和三乙胺(10.4mol)溶于DMF中得到反应液二；最后，将反应液一滴加到反应液二中，室温反应24小时结束反应。反应完后，过滤、旋干滤液，再经硅胶柱纯化得到8ARM-(EG 4-OTr) 4纯品。 To the three-necked bottle, octaacrylic acid was substituted for pentaerythritol tetraglyceride (Ib, 1 mol, prepared in Example 2) and NHS (8.8 mol), and then dissolved by stirring with DMF, and DCC (10.4 mol) was added thereto to react at room temperature overnight to obtain a reaction liquid 1; , weighed NH 2 (CH 2 CH 2 O) 4 Tr (9.6 mol) and triethylamine (10.4 mol) dissolved in DMF to obtain a reaction liquid 2; finally, a drop of the reaction solution was added to the reaction liquid 2, room temperature reaction The reaction was terminated in 24 hours. After the reaction, the filtrate was filtered, and the filtrate was dried, and then purified through silica gel column to obtain 8 ARM-(EG 4 -OTr) 4 pure product.

将8ARM-(EG 4-OTr) 4纯品溶于8％TFA的二氯甲烷溶液中，室温反应过夜，冰浴条件下加入适量0.1g/ml的氢氧化钠溶液，然后再室温反应3小时。反应结束后用1N盐酸调反应液pH值到6.5-7，然后加入适量氯化钠，二氯甲烷萃取两次，并旋干二氯甲烷相，然后加入适量水溶解二氯甲烷相旋干物，再过滤收集滤液，旋干滤液即得产品8ARM-(EG 4-OH) 4。 The 8ARM-(EG 4 -OTr) 4 pure product was dissolved in 8% TFA in dichloromethane, and reacted at room temperature overnight, and an appropriate amount of 0.1 g/ml sodium hydroxide solution was added under ice bath, and then reacted at room temperature for 3 hours. . After the reaction, the pH of the reaction solution was adjusted to 6.5-7 with 1N hydrochloric acid, then the appropriate amount of sodium chloride was added, and the mixture was extracted twice with dichloromethane, and the dichloromethane phase was spun, and then the appropriate amount of water was added to dissolve the dichloromethane. The filtrate was again collected by filtration, and the filtrate was dried to give the product 8ARM-(EG 4 -OH) 4 .

1H-NMR(DMSO-d 6)：2.27-2.33(m，16H)，3.16-3.20(m，16H)，3.28-3.44(m，24H)，3.48-3.50(m，116H)，3.55-3.60(m，8H)，3.66-3.70(m，8H)，4.56-4.59(t，8H)，7.87-7.90(t，8H)； 1 H-NMR (DMSO-d 6 ): 2.27-2.33 (m, 16H), 3.16-3.20 (m, 16H), 3.28-3.44 (m, 24H), 3.48-3.50 (m, 116H), 3.55-3. (m, 8H), 3.66-3.70 (m, 8H), 4.56-4.59 (t, 8H), 7.87-7.90 (t, 8H);

MALDI-TOF(2433.4，M+Na)。MALDI-TOF (2433.4, M+Na).

实施例6：合成四臂十二甘醇四缩水甘油醚(IIIa)Example 6: Synthesis of four-armed dodecaethylene glycol tetraglycidyl ether (IIIa)

合成如下结构的四臂十二甘醇四缩水甘油醚：The four-armed dodeca Glycol tetraglycidyl ether having the following structure was synthesized:

Figure PCTCN2018093523-appb-000065
Figure PCTCN2018093523-appb-000065

向三口瓶中加入4ARM-(EG 12-OH) 4(0.1mol，实施例4制备)、四氢呋喃(100mL)和氢氧化钾(0.8mol)，水浴搅拌，然后向反应体系中滴加环氧氯丙烷(ECH，1.2mol)，控制反应温度不超过35℃，室温反应过夜。反应完后过滤反应液，并用二氯甲烷洗涤滤渣，然后收集滤液，旋蒸除去二氯甲烷得到粗品。粗品经硅胶柱分后得到纯品十二甘醇四缩水甘油醚。 4ARM-(EG 12 -OH) 4 (0.1 mol, prepared in Example 4), tetrahydrofuran (100 mL) and potassium hydroxide (0.8 mol) were added to a three-necked flask, stirred in a water bath, and then an epoxy chloride was added dropwise to the reaction system. Propane (ECH, 1.2 mol), controlled to a temperature not exceeding 35 ° C, and allowed to react at room temperature overnight. After the reaction, the reaction solution was filtered, and the residue was washed with dichloromethane. The crude product was separated on a silica gel column to obtain pure dodecafurol tetraglycidyl ether.

1H-NMR(DMSO-d 6)：2.26-2.30(m，8H)，2.54-2.55(m，4H)，2.72-2.73(m，4H)，3.09-3.10(m，4H)，3.17-3.28(m，20H)，3.35-3.64(m，192H)，3.70-3.71(m，4H)，7.88-7.92(t，4H)； 1 H-NMR (DMSO-d 6 ): 2.26-2.30 (m, 8H), 2.54-2.55 (m, 4H), 2.72-2.73 (m, 4H), 3.09-3.10 (m, 4H), 3.17-3.28 (m, 20H), 3.35-3.64 (m, 192H), 3.70-3.71 (m, 4H), 7.88-7.92 (t, 4H);

MALDI-TOF(2780.3，M+Na)。MALDI-TOF (2780.3, M+Na).

实施例7：合成四臂二十四甘醇四缩水甘油醚(IIIb)Example 7: Synthesis of four-armed tetraethylene glycol tetraglycidyl ether (IIIb)

合成如下结构的四臂二十四甘醇四缩水甘油醚：The four-armed tetraethylene glycol tetraglycidyl ether having the following structure was synthesized:

Figure PCTCN2018093523-appb-000066
Figure PCTCN2018093523-appb-000066

Figure PCTCN2018093523-appb-000067
Figure PCTCN2018093523-appb-000067

向三口瓶中加入4ARM-(EG 24-OH) 4(0.1mol，实施例3制备)、四氢呋喃(100mL)和氢氧化钾(0.8mol)，水浴搅拌，然后向反应体系中滴加环氧氯丙烷(ECH，1.2mol)，控制反应温度不超过35℃，室温反应过夜。反应完后过滤反应液，并用二氯甲烷洗涤滤渣，然后收集滤液，旋蒸除去二氯甲烷得到粗品。粗品经硅胶柱分后得到纯品二十四甘醇四缩水甘油醚。 4ARM-(EG 24 -OH) 4 (0.1 mol, prepared in Example 3), tetrahydrofuran (100 mL) and potassium hydroxide (0.8 mol) were added to a three-necked flask, stirred in a water bath, and then an epoxy chloride was added dropwise to the reaction system. Propane (ECH, 1.2 mol), controlled to a temperature not exceeding 35 ° C, and allowed to react at room temperature overnight. After the reaction, the reaction solution was filtered, and the residue was washed with dichloromethane. The crude product was separated on a silica gel column to obtain pure tetraethylene glycol tetraglycidyl ether.

1H-NMR(DMSO-d 6)：2.26-2.30(m，8H)，2.54-2.55(m，4H)，2.72-2.73(m，4H)，3.09-3.10(m，4H)，3.17-3.28(m，20H)，3.35-3.64(m，384H)，3.70-3.71(m，4H)，7.88-7.92(t，4H)； 1 H-NMR (DMSO-d 6 ): 2.26-2.30 (m, 8H), 2.54-2.55 (m, 4H), 2.72-2.73 (m, 4H), 3.09-3.10 (m, 4H), 3.17-3.28 (m, 20H), 3.35-3.64 (m, 384H), 3.70-3.71 (m, 4H), 7.88-7.92 (t, 4H);

MALDI-TOF(4665.9，M+Na)。MALDI-TOF (4665.9, M+Na).

实施例8：合成八臂四甘醇八缩水甘油醚(IIIc)Example 8: Synthesis of eight-arm tetraethylene glycol octahydroglycidyl ether (IIIc)

合成如下结构的八臂四甘醇八缩水甘油醚：The eight-arm tetraethylene glycol octahydroglycidyl ether having the following structure was synthesized:

Figure PCTCN2018093523-appb-000068
Figure PCTCN2018093523-appb-000068

向三口瓶中加入8ARM-(EG 4-OH) 8(0.1mol，实施例5制备)、四氢呋喃(100mL)和氢氧化钾(1.6mol)，水浴搅拌，然后向反应体系中滴加环氧氯丙烷(ECH，2.4mol)，控制反应温度不超过35℃，室温反应过夜。反应完后过滤反应液，并用二氯甲烷洗涤滤渣，然后收集滤液，旋蒸除去二氯甲烷得到粗品。粗品经硅胶柱分后得到纯品八臂四甘醇八缩水甘油醚。 8ARM-(EG 4 -OH) 8 (0.1 mol, prepared in Example 5), tetrahydrofuran (100 mL) and potassium hydroxide (1.6 mol) were added to a three-necked flask, stirred in a water bath, and then an epoxy chloride was added dropwise to the reaction system. Propane (ECH, 2.4 mol), controlled to a temperature not exceeding 35 ° C, and allowed to react at room temperature overnight. After the reaction, the reaction solution was filtered, and the residue was washed with dichloromethane. The crude product was separated on a silica gel column to obtain pure eight-arm tetraethylene glycol octahydroglycidyl ether.

1H-NMR(DMSO-d 6)：2.27-2.33(m，16H)，2.54-2.55(m，8H)，2.72-2.73(m，8H)，3.09-3.10(m，8H)，3.16-3.26(m，24H)，3.28-3.44(m，24H)，3.48-3.50(m，116H)，3.55-3.60(m，8H)，3.66-3.71(m，16H)，7.87-7.90(t，8H)； 1 H-NMR (DMSO-d 6 ): 2.27-2.33 (m, 16H), 2.54-2.55 (m, 8H), 2.72-2.73 (m, 8H), 3.09-3.10 (m, 8H), 3.16-3.26 (m, 24H), 3.28-3.44 (m, 24H), 3.48-3.50 (m, 116H), 3.55-3.60 (m, 8H), 3.66-3.71 (m, 16H), 7.87-7.90 (t, 8H) ;

MALDI-TOF(2880.8，M+Na)。MALDI-TOF (2880.8, M+Na).

实施例9：合成四臂二十四甘醇-单乙酸(Ⅲd)和四臂二十四甘醇-二乙酸(Ⅲe)Example 9: Synthesis of four-armed tetraethylene glycol monoacetic acid (IIId) and four-armed tetraethylene glycol-diacetic acid (IIIe)

合成如下结构的四臂二十四甘醇-单乙酸：The four-armed tetraethylene glycol monoacetic acid having the following structure was synthesized:

[H(OCH 2CH 2) 24NHCOCH 2CH 2OCH 2] 3C[CH 2OCH 2CH 2CONH(CH 2CH 2O) 24CH 2COOH] [H(OCH 2 CH 2 ) 24 NHCOCH 2 CH 2 OCH 2 ] 3 C[CH 2 OCH 2 CH 2 CONH(CH 2 CH 2 O) 24 CH 2 COOH]

(Ⅲd)(IIId)

和如下结构的四臂二十四甘醇-二乙酸：And four-armed tetraethylene glycol-diacetic acid having the following structure:

[H(OCH 2CH 2) 24NHCOCH 2CH 2OCH 2] 2C[CH 2OCH 2CH 2CONH(CH 2CH 2O) 24CH 2COOH] 2 [H(OCH 2 CH 2 ) 24 NHCOCH 2 CH 2 OCH 2 ] 2 C[CH 2 OCH 2 CH 2 CONH(CH 2 CH 2 O) 24 CH 2 COOH] 2

(Ⅲe)(IIIe)

取4ARM-(EG 24-OH) 4(实施例3制备)，用甲苯除水，然后蒸出剩余甲苯，加入四氢呋喃，加入叔丁醇钾，室温下反应2小时，然后滴加溴乙酸叔丁酯，室温反应过夜，然后过滤，旋蒸浓缩滤液，然后加入NaOH溶液(1mol/L)，80度碱解2小时，然后用2N盐酸调节pH为2-3，然后加入NaCl，用二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，过滤，旋蒸浓缩。将粗品用DEAE阴离子交换树脂柱分离，分别收集不同馏分，可分别得到四臂二十四甘醇-单乙酸和四臂二十四甘醇-二乙酸馏分，产品结构通过 1H-NMR确定。 Take 4ARM-(EG 24 -OH) 4 (prepared in Example 3), remove water with toluene, then distill off the remaining toluene, add tetrahydrofuran, add potassium t-butoxide, react at room temperature for 2 hours, then add t-butyl bromoacetate The ester was reacted at room temperature overnight, then filtered, and the filtrate was concentrated by rotary evaporation, then NaOH solution (1 mol/L) was added, and alkalized at 80 degrees for 2 hours, then pH was adjusted to 2-3 with 2N hydrochloric acid, then NaCl was added thereto, and dichloromethane was used. It was extracted three times, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was separated by a DEAE anion exchange resin column, and different fractions were separately collected to obtain a four-arm twenty-four-glycol-monoacetic acid and a four-arm twenty-four-glycol-diacetic acid fraction, respectively, and the product structure was determined by 1 H-NMR.

Ⅲd： 1H-NMR(DMSO-d 6)：2.26-2.30(m，8H)，3.17-3.21(m，16H)，3.35-3.64(m，384H)，4.01(s，2H)，4.58-4.62(t，3H)，7.90-7.94(t，4H)； IIId: 1 H-NMR (DMSO-d 6 ): 2.26-2.30 (m, 8H), 3.17-3.21 (m, 16H), 3.35-3.64 (m, 384H), 4.01 (s, 2H), 4.58-4.62 (t, 3H), 7.90-7.94 (t, 4H);

MALDI-TOF(4729.4，M+Na)。MALDI-TOF (4729.4, M+Na).

Ⅲe： 1H-NMR(DMSO-d 6)：2.27-2.30(m，8H)，3.17-3.20(m，16H)，3.36-3.64(m，384H)，4.02(s，4H)，4.59-4.62(t，2H)，7.92-7.94(t，4H)； IIIe: 1 H-NMR (DMSO-d 6 ): 2.27-2.30 (m, 8H), 3.17-3.20 (m, 16H), 3.36-3.64 (m, 384H), 4.02 (s, 4H), 4.59-4.62 (t, 2H), 7.92-7.94 (t, 4H);

MALDI-TOF(4787.5，M+Na)。MALDI-TOF (4787.5, M+Na).

以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换等，均应包含在本发明的保护范围之内。The above is only the preferred embodiment of the present invention, and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc., which are within the spirit and principles of the present invention, should be included in the scope of the present invention. within.

Claims (24)

一种化合物，其具有如下结构：A compound having the structure:
Figure PCTCN2018093523-appb-100001
Figure PCTCN2018093523-appb-100001
 其中，A为核心结构，为多元醇基，选自：季戊四醇、寡聚季戊四醇、丙三醇和寡聚丙三醇的残基及其甘油醚基，Wherein A is a core structure and is a polyol group selected from the group consisting of: pentaerythritol, oligo-pentaerythritol, glycerol and oligoglycerol residues and glyceryl ether groups thereof, X 1为连接基团，选自：-(CH 2) i-、-(CH 2) iO-、-(CH 2) iNHCO-、-(CH 2) iCONH-、-(CH 2) iOCO-和-(CH 2) iCOO-中一种或两种以上的组合，i为1-10的整数， X 1 is a linking group selected from the group consisting of: -(CH 2 ) i -, -(CH 2 ) i O-, -(CH 2 ) i NHCO-, -(CH 2 ) i CONH-, -(CH 2 ) a combination of one or more of i OCO- and -(CH 2 ) i COO-, i is an integer from 1 to 10, Y为端基，选自：氢、羟基、羧基、酯基、酮基、氨基、巯基、马来酰亚胺基、炔基和叠氮基中的一种，Y is a terminal group selected from the group consisting of hydrogen, a hydroxyl group, a carboxyl group, an ester group, a ketone group, an amino group, a fluorenyl group, a maleimide group, an alkynyl group, and an azide group. n为3-24的整数。n is an integer from 3 to 24. 如权利要求1所述的化合物，其特征在于，所述A具有如下结构：The compound of claim 1 wherein said A has the structure:
Figure PCTCN2018093523-appb-100002
Figure PCTCN2018093523-appb-100002
 其中，B具有如下结构：
Figure PCTCN2018093523-appb-100003
Among them, B has the following structure:
Figure PCTCN2018093523-appb-100003
 r为1-5的整数，优选地，所述r为1、2或3，r is an integer from 1 to 5, preferably, the r is 1, 2 or 3, a、b、c和d为整数，独立地选自0和1，a, b, c and d are integers, independently selected from 0 and 1, s为1-5的整数，优选地，所述s为1、2或3，s is an integer from 1 to 5, preferably, the s is 1, 2 or 3, e、f和g为整数，独立地选自0和1；e, f and g are integers, independently selected from 0 and 1; 优选地，所述a、b、c和d均为0，或，所述a、b、c和d均为1；Preferably, the a, b, c and d are both 0, or the a, b, c and d are both 1; 优选地，所述e、f和g均为0，或，所述e、f和g均为1。Preferably, the e, f and g are both 0, or the e, f and g are both 1. 如权利要求1或2所述的化合物，其特征在于，所述A选自如下结构：The compound according to claim 1 or 2, wherein the A is selected from the following structures:
Figure PCTCN2018093523-appb-100004
Figure PCTCN2018093523-appb-100004
Figure PCTCN2018093523-appb-100005
Figure PCTCN2018093523-appb-100005
 如权利要求1-3任一项所述的化合物，其特征在于，所述X 1选自：-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH 2CONHCH 2-和-CH 2CONHCH 2CH 2-中一种或两种以上的组合；和/或， The compound according to any one of claims 1 to 3, wherein the X 1 is selected from the group consisting of: -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CONHCH One or a combination of two or more of 2- and -CH 2 CONHCH 2 CH 2 -; and/or, 所述Y中，所述酯基选自：
Figure PCTCN2018093523-appb-100006
Figure PCTCN2018093523-appb-100007
中的一种；和/或， In the Y, the ester group is selected from the group consisting of:
Figure PCTCN2018093523-appb-100006
Figure PCTCN2018093523-appb-100007
One of them; and/or, 所述Y中，所述酮基选自：
Figure PCTCN2018093523-appb-100008
-COCH 3和-COCH 2CH 3中的一种。 In the Y, the ketone group is selected from the group consisting of:
Figure PCTCN2018093523-appb-100008
One of -COCH 3 and -COCH 2 CH 3 . 如权利要求1-3任一项所述的化合物，其特征在于，所述X 1为-CH 2CH 2-；和/或，所述Y为-COOH。 The compound according to any one of claims 1 to 3, wherein X 1 is -CH 2 CH 2 -; and/or Y is -COOH. 如权利要求5所述的化合物，其特征在于，所述的化合物选自如下结构：The compound of claim 5 wherein said compound is selected from the group consisting of:
Figure PCTCN2018093523-appb-100009
Figure PCTCN2018093523-appb-100009
Figure PCTCN2018093523-appb-100010
Figure PCTCN2018093523-appb-100010
 一种多臂单一分子量聚乙二醇，其具有如下结构：A multi-arm single molecular weight polyethylene glycol having the following structure:
Figure PCTCN2018093523-appb-100011
Figure PCTCN2018093523-appb-100011
 其中，A为核心结构，为多元醇基，选自：季戊四醇、寡聚季戊四醇、丙三醇和寡聚丙三醇的残基及其甘油醚基，Wherein A is a core structure and is a polyol group selected from the group consisting of: pentaerythritol, oligo-pentaerythritol, glycerol and oligoglycerol residues and glyceryl ether groups thereof, X 1为连接基团，选自：-(CH 2) i-、-(CH 2) iO-、-(CH 2) iNHCO-、-(CH 2) iCONH-、-(CH 2) iOCO-和-(CH 2) iCOO-中一种或两种以上的组合，i为1-10的整数， X 1 is a linking group selected from the group consisting of: -(CH 2 ) i -, -(CH 2 ) i O-, -(CH 2 ) i NHCO-, -(CH 2 ) i CONH-, -(CH 2 ) a combination of one or more of i OCO- and -(CH 2 ) i COO-, i is an integer from 1 to 10, R为连接基团，选自：-NHCO-、-CONH-、-OCO-、-COO-、-O-、
Figure PCTCN2018093523-appb-100012
Figure PCTCN2018093523-appb-100013
中一种或两种以上的组合， R is a linking group selected from the group consisting of: -NHCO-, -CONH-, -OCO-, -COO-, -O-,
Figure PCTCN2018093523-appb-100012
Figure PCTCN2018093523-appb-100013
One or a combination of two or more, X 2为连接基团，选自：-(CH 2) j-、-(CH 2) jO-、-(CH 2) jCO-、-(CH 2) jNH-、-(CH 2) jNHCO-、-(CH 2) jCONH-、-(CH 2) jOCO-和-(CH 2) jCOO-中一种或两种以上的组合，j为0-10的整数， X 2 is a linking group selected from the group consisting of: -(CH 2 ) j -, -(CH 2 ) j O-, -(CH 2 ) j CO-, -(CH 2 ) j NH-, -(CH 2 ) j NHCO-, -(CH 2 ) j CONH-, -(CH 2 ) j OCO- and -(CH 2 ) j COO- one or a combination of two or more, j is an integer from 0 to 10, PEG具有如下结构：-(CH 2CH 2O) m-，m为4-200的整数， PEG has the following structure: -(CH 2 CH 2 O) m -, m is an integer from 4 to 200, n为3-24的整数。n is an integer from 3 to 24. 如权利要求7所述的多臂单一分子量聚乙二醇，其特征在于，所述A具有如下结构：The multi-arm single molecular weight polyethylene glycol according to claim 7, wherein said A has the following structure:
Figure PCTCN2018093523-appb-100014
Figure PCTCN2018093523-appb-100014
 其中，B具有如下结构：
Figure PCTCN2018093523-appb-100015
Among them, B has the following structure:
Figure PCTCN2018093523-appb-100015
 r为1-5的整数，优选地，所述r为1、2或3，r is an integer from 1 to 5, preferably, the r is 1, 2 or 3, a、b、c和d为整数，独立地选自0和1，a, b, c and d are integers, independently selected from 0 and 1, s为1-5的整数，优选地，所述s为1、2或3s is an integer from 1 to 5, preferably, the s is 1, 2 or 3 e、f和g为整数，独立地选自0和1；e, f and g are integers, independently selected from 0 and 1; 优选地，所述a、b、c和d均为0，或，所述a、b、c和d均为1；Preferably, the a, b, c and d are both 0, or the a, b, c and d are both 1; 优选地，所述e、f和g均为0，或所述e、f和g均为1。Preferably, the e, f and g are both 0, or the e, f and g are both 1. 如权利要求7或8所述的多臂单一分子量聚乙二醇，其特征在于，所述A选自如下结构：The multi-arm single molecular weight polyethylene glycol according to claim 7 or 8, wherein the A is selected from the following structures:
Figure PCTCN2018093523-appb-100016
Figure PCTCN2018093523-appb-100016
 如权利要求7-9任一项所述的多臂单一分子量聚乙二醇，其特征在于，所述X 1选自：-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH 2CONHCH 2-和-CH 2CONHCH 2CH 2-中一种或两种以上的组合；和/或， The multi-arm single molecular weight polyethylene glycol according to any one of claims 7 to 9, wherein the X 1 is selected from the group consisting of: -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH One or a combination of two or more of 2- , -CH 2 CONHCH 2 - and -CH 2 CONHCH 2 CH 2 -; and/or, 所述R选自：-NHCO-、-CONH-、
Figure PCTCN2018093523-appb-100017
中一种或两种以上的组合；和/或， The R is selected from the group consisting of: -NHCO-, -CONH-,
Figure PCTCN2018093523-appb-100017
One or a combination of two or more; and/or, 所述X 2选自：单键、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH 2CONHCH 2-和-CH 2CONHCH 2CH 2-中一种或两种以上的组合；和/或， The X 2 is selected from the group consisting of: a single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CONHCH 2 -, and -CH 2 CONHCH 2 CH 2 - Combination of two or more; and / or, 所述m为4-100的整数。The m is an integer from 4 to 100. 如权利要求7-10任一项所述的多臂单一分子量聚乙二醇，其特征在于，所述X 1为-CH 2CH 2-；和/或，所述R为-NHCO-或-CONH-；和/或，所述X 2为单键；和/或，所述m为4、12或24。 The multi-arm single molecular weight polyethylene glycol according to any one of claims 7 to 10, wherein X 1 is -CH 2 CH 2 -; and/or R is -NHCO- or - CONH-; and/or, said X 2 is a single bond; and/or said m is 4, 12 or 24. 如权利要求11所述的多臂单一分子量聚乙二醇，其特征在于，所述多臂单一分子量聚乙二醇选自如下结构：The multi-arm single molecular weight polyethylene glycol according to claim 11, wherein the multi-arm single molecular weight polyethylene glycol is selected from the following structures:
Figure PCTCN2018093523-appb-100018
Figure PCTCN2018093523-appb-100018
Figure PCTCN2018093523-appb-100019
Figure PCTCN2018093523-appb-100019
 一种权利要求7-12任一项所述的多臂单一分子量聚乙二醇的制备方法，所述方法包括权利要求1-9任一项所述的化合物
Figure PCTCN2018093523-appb-100020
与W-X 2-PEG-PG进行反应连接的步骤，反应通式如下： A method for preparing a multi-arm single molecular weight polyethylene glycol according to any one of claims 7 to 12, which comprises the compound according to any one of claims 1-9
Figure PCTCN2018093523-appb-100020
The step of reacting with WX 2 -PEG-PG, the reaction formula is as follows:
Figure PCTCN2018093523-appb-100021
Figure PCTCN2018093523-appb-100021
 其中，W为端基，选自：氢、羟基、羧基、酯基、酮基、氨基、巯基、马来酰亚胺基、炔基和叠氮基中的一种，Wherein W is a terminal group selected from the group consisting of hydrogen, a hydroxyl group, a carboxyl group, an ester group, a ketone group, an amino group, a thiol group, a maleimide group, an alkynyl group, and an azide group. PG为羟基保护基团；PG is a hydroxy protecting group; 优选地，所述Y为羧基，所述W为氨基，或，所述Y为氨基，所述W为羧基。Preferably, the Y is a carboxyl group, the W is an amino group, or the Y is an amino group, and the W is a carboxyl group. 一种多臂单一分子量聚乙二醇活性衍生物，其具有如下结构：A multi-arm single molecular weight polyethylene glycol active derivative having the following structure:
Figure PCTCN2018093523-appb-100022
Figure PCTCN2018093523-appb-100022
 其中，A为核心结构，为多元醇基，选自：季戊四醇、寡聚季戊四醇、丙三醇和寡聚丙三醇的残基及其甘油醚基，Wherein A is a core structure and is a polyol group selected from the group consisting of: pentaerythritol, oligo-pentaerythritol, glycerol and oligoglycerol residues and glyceryl ether groups thereof, X 1为连接基团，选自：-(CH 2) i-、-(CH 2) iO-、-(CH 2) iNHCO-、-(CH 2) iCONH-、-(CH 2) iOCO-和-(CH 2) iCOO-中一种或两种以上的组合，i为1-10的整数， X 1 is a linking group selected from the group consisting of: -(CH 2 ) i -, -(CH 2 ) i O-, -(CH 2 ) i NHCO-, -(CH 2 ) i CONH-, -(CH 2 ) a combination of one or more of i OCO- and -(CH 2 ) i COO-, i is an integer from 1 to 10, R为连接基团，选自：-NHCO-、-CONH-、-OCO-、-COO-、-O-、
Figure PCTCN2018093523-appb-100023
Figure PCTCN2018093523-appb-100024
中一种或两种以上的组合， R is a linking group selected from the group consisting of: -NHCO-, -CONH-, -OCO-, -COO-, -O-,
Figure PCTCN2018093523-appb-100023
Figure PCTCN2018093523-appb-100024
One or a combination of two or more, X 2为连接基团，选自：-(CH 2) j-、-(CH 2) jO-、-(CH 2) jCO-、-(CH 2) jNH-、-(CH 2) jNHCO-、-(CH 2) jCONH-、-(CH 2) jOCO-和-(CH 2) jCOO-中一种或两种以上的组合，j为0-10的整数， X 2 is a linking group selected from the group consisting of: -(CH 2 ) j -, -(CH 2 ) j O-, -(CH 2 ) j CO-, -(CH 2 ) j NH-, -(CH 2 ) j NHCO-, -(CH 2 ) j CONH-, -(CH 2 ) j OCO- and -(CH 2 ) j COO- one or a combination of two or more, j is an integer from 0 to 10, PEG具有如下结构：-(CH 2CH 2O) m-，m为4-200的整数， PEG has the following structure: -(CH 2 CH 2 O) m -, m is an integer from 4 to 200, F为相同或不同的-X 3-Z型结构， F is the same or different -X 3 -Z structure, X 3为连接基团，选自：-(CH 2) k-、-(CH 2) kO-、-(CH 2) kCO-、-(CH 2) kNH-、-(CH 2) kNHCO-、-(CH 2) kCONH-、-(CH 2) kNHCONH-、-(CH 2) kOCO-、-(CH 2) kCOO-、-(CH 2) kOCOO-和-(CH 2) kOCONH-中一种或两种以上的组合，k为0-10的整数， X 3 is a linking group selected from the group consisting of: -(CH 2 ) k -, -(CH 2 ) k O-, -(CH 2 ) k CO-, -(CH 2 ) k NH-, -(CH 2 ) k NHCO -, - (CH 2 ) k CONH -, - (CH 2) k NHCONH -, - (CH 2) k OCO -, - (CH 2) k COO -, - (CH 2) k OCOO- and - (CH 2 ) k OCONH- one or a combination of two or more, k is an integer from 0 to 10, Z为活性端基，选自：-H、-NH 2、-ONH 2、-SH、-N 3、-Br、-CONH 2、-CONHNH 2、-COONH 2、-COOH、-PO 3H、-CHO、-CO-HA、-C≡CH、
Figure PCTCN2018093523-appb-100025
-COCH＝CH 2、-COC(CH 3)＝CH 2、-CN、-CH 2CH＝CH 2、-CH＝CH-COOH、-N＝C＝O、
Figure PCTCN2018093523-appb-100026
Figure PCTCN2018093523-appb-100027
Figure PCTCN2018093523-appb-100028
C1-6的烷基和C1-6的烷氧基中的一种， Z is a reactive end group selected from the group consisting of: -H, -NH 2 , -ONH 2 , -SH, -N 3 , -Br, -CONH 2 , -CONHNH 2 , -COONH 2 , -COOH, -PO 3 H, -CHO, -CO-HA, -C≡CH,
Figure PCTCN2018093523-appb-100025
-COCH=CH 2 , -COC(CH 3 )=CH 2 , -CN, -CH 2 CH=CH 2 , -CH=CH-COOH, -N=C=O,
Figure PCTCN2018093523-appb-100026
Figure PCTCN2018093523-appb-100027
Figure PCTCN2018093523-appb-100028
One of a C1-6 alkyl group and a C1-6 alkoxy group, HA为卤原子，HA is a halogen atom, E为C1-10烃基或含氟原子的C1-10的烃基，E is a C1-10 hydrocarbon group or a fluorine atom-containing C1-10 hydrocarbon group, L 1-3为相同或不同的C1-10的烷基或C1-6的烷氧基， L 1-3 is the same or different C1-10 alkyl group or C1-6 alkoxy group, n为3-24的整数。n is an integer from 3 to 24. 如权利要求14所述的活性衍生物，其特征在于，所述A具有如下结构：The living derivative according to claim 14, wherein said A has the following structure:
Figure PCTCN2018093523-appb-100029
Figure PCTCN2018093523-appb-100029
 其中，B具有如下结构：
Figure PCTCN2018093523-appb-100030
Among them, B has the following structure:
Figure PCTCN2018093523-appb-100030
 r为1-5的整数，优选地，所述r为1、2或3，r is an integer from 1 to 5, preferably, the r is 1, 2 or 3, a、b、c和d为整数，独立地选自0和1，a, b, c and d are integers, independently selected from 0 and 1, s为1-5的整数，优选地，所述s为1、2或3，s is an integer from 1 to 5, preferably, the s is 1, 2 or 3, e、f和g为整数，独立地选自0和1；e, f and g are integers, independently selected from 0 and 1; 优选地，所述a、b、c和d均为0，或，所述a、b、c和d均为1；Preferably, the a, b, c and d are both 0, or the a, b, c and d are both 1; 优选地，所述e、f和g均为0，或所述e、f和g均为1。Preferably, the e, f and g are both 0, or the e, f and g are both 1. 如权利要求14或15所述的活性衍生物，其特征在于，所述A选自如下结构：The active derivative according to claim 14 or 15, wherein the A is selected from the following structures:
Figure PCTCN2018093523-appb-100031
Figure PCTCN2018093523-appb-100031
 如权利要求14-16任一项所述的活性衍生物，其特征在于，所述X 1选自：-CH 2-、-CH 2CH 2-、 -CH 2CH 2CH 2-、-CH 2CONHCH 2-和-CH 2CONHCH 2CH 2-中一种或两种以上的组合；和/或， The reactive derivative according to any one of claims 14-16, wherein said X 1 is selected from the group consisting of: -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 a combination of one or more of CONHCH 2 - and -CH 2 CONHCH 2 CH 2 -; and/or, 所述R选自：-NHCO-、-CONH-、
Figure PCTCN2018093523-appb-100032
中一种或两种以上的组合；和/或， The R is selected from the group consisting of: -NHCO-, -CONH-,
Figure PCTCN2018093523-appb-100032
One or a combination of two or more; and/or, 所述X 2选自：单键、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH 2CONHCH 2-和-CH 2CONHCH 2CH 2-中一种或两种以上的组合；和/或， The X 2 is selected from the group consisting of: a single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CONHCH 2 -, and -CH 2 CONHCH 2 CH 2 - Combination of two or more; and / or, 所述X 3选自：单键、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH 2O-、-CH 2CH 2O-、-CH 2CONHCH 2-和-CH 2CONHCH 2CH 2-中一种或两种以上的组合；和/或， The X 3 is selected from the group consisting of: a single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 O-, -CH 2 CH 2 O-, -CH 2 CONHCH 2 - and -CH 2 CONHCH 2 CH 2 - one or a combination of two or more; and / or, 所述Z选自：-H、-NH 2、-SH、-N 3、-Br、-CONH 2、-COOH、-CHO、-COCl、-COBr、-C≡CH、
Figure PCTCN2018093523-appb-100033
Figure PCTCN2018093523-appb-100034
Figure PCTCN2018093523-appb-100035
中的一种；和/或， The Z is selected from the group consisting of: -H, -NH 2 , -SH, -N 3 , -Br, -CONH 2 , -COOH, -CHO, -COCl, -COBr, -C≡CH,
Figure PCTCN2018093523-appb-100033
Figure PCTCN2018093523-appb-100034
Figure PCTCN2018093523-appb-100035
One of them; and/or, 所述m为4-100的整数。The m is an integer from 4 to 100. 如权利要求14-17任一项所述的活性衍生物，其特征在于，所述X 1为-CH 2CH 2-；和/或，所述R为-NHCO-或-CONH-；和/或，所述X 2为单键；和/或，所述X 3为单键或-CH 2-；和/或，所述m为4、12或24。 The reactive derivative according to any one of claims 14-17, wherein X 1 is -CH 2 CH 2 -; and/or R is -NHCO- or -CONH-; Or, X 2 is a single bond; and/or X 3 is a single bond or -CH 2 -; and/or m is 4, 12 or 24. 如权利要求14-18任一项所述的活性衍生物，其特征在于，所述F为
Figure PCTCN2018093523-appb-100036
或，所述F包括-H和-CH 2COOH。 The reactive derivative according to any one of claims 14 to 18, wherein said F is
Figure PCTCN2018093523-appb-100036
Or, the F includes -H and -CH 2 COOH. 如权利要求14所述的活性衍生物，其特征在于，所述多臂单一分子量聚乙二醇活性衍生物选自如下结构：The reactive derivative according to claim 14, wherein the multi-arm single molecular weight polyethylene glycol active derivative is selected from the group consisting of the following structures:
Figure PCTCN2018093523-appb-100037
Figure PCTCN2018093523-appb-100037
 F 11-14为相同或不同的-X 3-Z型结构； F 11-14 is the same or different -X 3 -Z type structure;
Figure PCTCN2018093523-appb-100038
Figure PCTCN2018093523-appb-100038
 F 21-26为相同或不同的-X 3-Z型结构； F 21-26 is the same or different -X 3 -Z structure;
Figure PCTCN2018093523-appb-100039
Figure PCTCN2018093523-appb-100039
 F 31-38为相同或不同的-X 3-Z型结构； F 31-38 are the same or different -X 3 -Z type structures;
Figure PCTCN2018093523-appb-100040
Figure PCTCN2018093523-appb-100040
 F 41-48为相同或不同的-X 3-Z型结构； F 41-48 are the same or different -X 3 -Z structure;
Figure PCTCN2018093523-appb-100041
Figure PCTCN2018093523-appb-100041
 F 51-53为相同或不同的-X 3-Z型结构； F 51-53 is the same or different -X 3 -Z type structure;
Figure PCTCN2018093523-appb-100042
Figure PCTCN2018093523-appb-100042
 F 61-64为相同或不同的-X 3-Z型结构。 F 61-64 are the same or different -X 3 -Z type structures. 如权利要求20所述的活性衍生物，其特征在于，式Ⅴ-1中，所述m为12或24，所述F 11-14均为
Figure PCTCN2018093523-appb-100043
或， The reactive derivative according to claim 20, wherein in the formula V-1, the m is 12 or 24, and the F 11-14 is
Figure PCTCN2018093523-appb-100043
or, 式Ⅴ-1中，所述m为24，所述F 11-13均为-H，所述F 14为-CH 2COOH，或， In the formula V-1, the m is 24, the F 11-13 is -H, and the F 14 is -CH 2 COOH, or 式Ⅴ-1中，所述m为24，所述F 11和F 12为-H，所述F 13和F 14为-CH 2COOH，或， In the formula V-1, the m is 24, the F 11 and F 12 are -H, and the F 13 and F 14 are -CH 2 COOH, or, 式Ⅴ-4中，所述F 41-48均为
Figure PCTCN2018093523-appb-100044
In Formula V-4, the F 41-48 is
Figure PCTCN2018093523-appb-100044
 一种权利要求14-21任一项所述的活性衍生物形成的凝胶。A gel formed from the active derivative of any of claims 14-21. 一种权利要求7-12任一项所述的多臂单一分子量聚乙二醇或权利要求14-21任一项所述的活性衍生物与药物分子的结合物。A multi-arm single molecular weight polyethylene glycol according to any one of claims 7 to 12, or a combination of the active derivative according to any one of claims 14 to 21 and a drug molecule. 一种包含权利要求23所述的结合物与药学上可接受的添加剂的药物组合物。A pharmaceutical composition comprising the conjugate of claim 23 and a pharmaceutically acceptable additive.
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